Williams Hematology



Basic Principles of Cancer Chemotherapy

Combination Chemotherapy

Cell Kinetics and Cancer Chemotherapy

Drug Resistance
Cell Cycle-Active Agents


Cytosine Arabinoside (Cytarabine)


Purine Analogs

Fludarabine Phosphate

2-Chlorodeoxyadenosine (Cladribine)

2-Deoxycoformycin (Pentostatin)


The Vinca Alkaloids



Anthracycline Antibiotics



Agents Active throughout the Cell Cycle

The Alkylating Drugs
Differentiating Agents


Arsenic Trioxide
Chapter References

The safe and effective use of anticancer drugs in the treatment of hematological malignancies requires an in-depth knowledge of the pharmacology of these agents. In no other field of medicine is the margin of safety more narrow or the potential for serious if not fatal toxicity more real. At the same time, anticancer drugs are capable of curing many of these otherwise aggressive malignancies, and their discovery and development have provided a paradigm for approaches to the improved treatment of the more common solid tumors.
The intelligent use of these drugs begins with an understanding of their mechanism of action. Most anticancer drugs inhibit the synthesis of DNA or directly attack the integrity of DNA through the formation of DNA adducts or enzyme-mediated breaks. These DNA-directed actions are recognized by repair processes and by the checkpoints that monitor DNA integrity, including most prominently p53. If DNA damage can not be repaired, and if the DNA damage reaches thresholds for activating programmed cell death, then DNA damage is translated into tumor regression. Resistance to drug action can arise from alterations in any one of the critical steps required for drug activity; these steps include drug transport in the blood stream or across the blood-brain barrier, transport across the cell membrane, transformation of the parent drug to its active form within the tumor cell or in the liver, interaction of the drug with its target protein or nucleic acid, enzymatic or chemical inactivation of the agent and its transport out of the cell, and elimination of the agent from the body through the kidneys or bile. The underlying mutability of tumors leads to the generation of cells with alterations in one or more of these critical steps in drug action, leading to the selection and outgrowth of drug-resistant tumor. Combination chemotherapy logically evades resistance that carries specificity for single agents, but increasingly, research has revealed mutations that lead to multidrug resistance (MDR), including overexpression of transporters such as the multidrug resistance (MDR) gene, as well as loss of the apoptotic response.
In addition to the molecular determinants of drug action, pharmacokinetics (the disposition of drugs in humans) play a critical role in determining drug effectiveness and toxicity. Because of the potential of these agents for toxicity, it is critical for oncologists to understand the pathways of drug clearance and to adjust dose in the presence of compromised organ function. Drugs such as methotrexate, hydroxyurea, and the newer purine antagonists (fludarabine and cladribine) are eliminated primarily by renal excretion and should not be used in full doses in patients with renal dysfunction. Similarly, hepatic dysfunction with elevated serum bilirubin concentrations should alert clinicians to decrease doses of the taxanes, vinca alkaloids, and (with less certainty) the anthracyclines. In addition, clinicians must be alert to the potential for drug interactions, particularly the ability of drugs that induce CYP 3A4 and CYP 2B6 to accelerate the metabolism of paclitaxel and of allopurinol to inhibit the metabolic breakdown of orally administered 6-mercaptopurine.
Clinicians must be alert to the potential for genetically determined differences in drug toxicity and response. The most important of these familial syndromes affecting treatment of leukemia is the deficiency of thiopurine methyltransferase, which slows the elimination of 6-mercaptopurine and leads to unanticipated toxicity during maintenance chemotherapy for acute lymphocytic leukemia. Pharmacokinetic monitoring has a standard role in the use of certain therapies, particularly high-dose methotrexate, and in the evaluation of new drugs or new drug combinations. Major cancer centers must have the capability of performing pharmacokinetic studies in conjunction with their clinical research programs.
To assure appropriate dose reduction, regimen choice, and management of toxicity, there is no substitute for therapy based on standard protocols and peer reviewed clinical trials. Adherence to protocols assures that the pharmacologic and pharmacogenetic variables affecting cancer chemotherapy can be recognized early in the course of treatment and that serious untoward events can be avoided while maintaining effective therapy.

Portions of this chapter are based on Chapter 28, by Joseph Bertino, in the fourth edition of this book.
Acronyms and abbreviations that appear in this chapter include: ABVD, Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine; APL, acute promyelocytic leukemia; ADH, antidiuretic hormone; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; ara-C, cytosine arabinoside; ara-U, uracil arabinoside; BCNU, bischloroethylnitrosourea; CDA, chlorodeoxyadenosine; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CYP, cytochrome P450; DCF, deoxycoformycin; DHFR, dihydrofolate reductase; HPRT, hypoxanthine-guanine phosphoribosyl transferase; IL, interleukin; MDR, multidrug resistance; MP, mercaptopurine; MRP, multidrug resistance–associated protein; MTD, maximum tolerated dose; RAR-a, retinoic acid-a receptor; TG, thioguanine; TGB, transforming growth factor; tRA, all-trans-retinoic acid.

The leukemias and lymphomas have been the proving ground for chemotherapy. The first evidence for antitumor activity of a chemical agent came from experiments with nitrogen mustard in a patient with Hodgkin disease in 1942.1 The even more startling discovery of remission induction by antifolates in acute lymphocytic leukemia 6 years later ushered in the era of chemotherapy in cancer treatment.2 Subsequent clinical experiments in these diseases established the basic principles of cyclic combination therapy and dose intensification, developed effective strategies for marrow transplantation, and demonstrated the importance of specific mechanisms of drug resistance. These principles have led to curative regimens for acute leukemias and lymphomas, effective therapies for chronic leukemias and multiple myeloma, and they have provided the conceptual basis for the current practice of medical oncology.
The safe and effective use of chemotherapy in clinical practice requires a thorough understanding of the basic aspects of drug action as well as knowledge of the important clinical toxicities, pharmacokinetics, and drug interactions. Antineoplastic chemotherapy is often complex, and there is the potential for serious or fatal side effects. Patients are best served, usually, if their treatment is derived from the recommendations made from clinical trials. The modification of doses and schedules of drug administration should be made, where possible, on the recommendations derived from clinical trials. The choice of a specific protocol of treatment should depend not only on the stage and histology of the tumor but on an assessment of individual patient tolerance and susceptibility to specific potential toxicities. Thus, bleomycin would not usually be an appropriate choice for a patient with serious underlying lung disease, nor would doxorubicin be an appropriate drug for use in a patient with a history of congestive heart failure.
With the development of techniques for marrow or blood stem cell storage and reinfusion, previously fatal doses of chemotherapy can be administered in an attempt to cure malignancies refractory to standard chemotherapy. In general, these regimens produce a spectrum of organ toxicities not seen at conventional doses—including pulmonary dysfunction, cardiac failure, and hepatic and renal insufficiency—and are ordinarily reserved for patients of younger age and with normal baseline organ function3 (see Chap. 18).
Since the malignant process is characterized by uncontrolled proliferation, it is logical that chemotherapy should target DNA replication. Most effective cancer drugs either interfere with the synthesis of DNA or produce chemical lesions in DNA. The mechanism by which most drugs cause cell death is unclear. In some cells apoptosis, or programmed cell death, follows exposure to cytotoxic agents, whereas other cells may proceed through mitosis before dying. The greater susceptibility of malignant cells to drug toxicity, while evident in the course of remission induction, cannot be explained at present but may result from the existence of normal stem cells in a nonreplicating phase of the cell cycle, where they are less susceptible to damage by DNA-directed agents. In addition, there is growing evidence that cancer cells lack the normal checkpoints in the cell cycle that would otherwise block the entry of damaged cells into DNA synthesis and mitosis and would thus allow repair of DNA strand breaks, base deletions, or other lesions induced by chemotherapy.4 These factors allow normal cells to escape with less intrinsic damage and favor their recovery from chemotherapy-induced injury. While most antimetabolites and alkylating agents target DNA, other drugs attack the mitotic spindle (vinca alkaloids), inhibit protein synthesis (L-asparaginase), or induce cell differentiation (all-trans-retinoic acid). Cancer drug discovery efforts have evolved and now target a number of specific processes fundamental to tumor initiation or progression, including receptor signaling, intracellular signal transduction, angiogenesis, and metastasis.5
While most leukemias and lymphomas are highly drug sensitive, with the exception of Burkitt lymphoma treated with cyclophosphamide, these tumors are rarely cured with single-agent chemotherapy. Combination chemotherapy has proven to be much more effective in forestalling the emergence of drug-resistant cells and thus has curative potential in settings where individual agents are ineffective. Certain empirical principles have resulted from the clinical experience of the past four decades of combination therapy. Drugs selected for combination therapy should, with few exceptions (such as the rescue agent leucovorin), have demonstrable antineoplastic activity of their own against the tumor in question. The individual agents should have different mechanisms of action and should not share a common mechanism of resistance such as MDR. The dose-limiting toxicities of the agents chosen should not overlap; otherwise, they could not be used together at or near full doses. Finally, the clinical use of specific combinations should be designed on preclinical evidence of synergistic interaction. Favorable drug interactions may be very dependent on specific sequences and schedules of administration. For these reasons, clinical protocols should attempt to duplicate the most favorable preclinical regimens.
Another important consideration in designing clinical protocols is dose intensity, the dose administered per unit time, which should be maintained throughout a treatment regimen. Achieving this objective may require the use of hematopoietic growth factors to hasten marrow recovery, prevent repeated episodes of febrile neutropenia, and allow on-time administration of the next treatment cycle. Interdigitation of chemotherapy with surgery and irradiation makes it possible to take advantage of favorable cytokinetic or radiosensitizing effects of chemotherapy, while avoiding enhancement of toxicity. Thus, 5-fluorouracil and cisplatin are used with radiation therapy to enhance local tumor control in malignancies of the head and neck,6 esophagus,7 and anus.8 Surgical reduction of tumor bulk increases the response rate of ovarian tumors to chemotherapy, perhaps by eliminating poorly perfused tumor masses.9 In the treatment of lymphomas, the toxicity of radiation therapy to sensitive organs such as skin, lung, heart, and brain may be significantly increased by concurrent administration of anthracyclines, a consideration that has prompted the use of radiation therapy either separated from or sandwiched between cycles of chemotherapy that include doxorubicin.
The cell-killing characteristics of cancer chemotherapeutic agents vary according to their mechanism of action. Many of the most effective agents in antileukemic therapy belong to the antimetabolite class, including cytosine arabinoside, 6-thioguanine, and methotrexate. These drugs kill cells most effectively during the DNA-synthetic phase (S phase) of the cell cycle. They have greatly diminished toxicity for nondividing cells. For these agents, a prolonged period of tumor exposure to drug is essential in order to maximize the number of cells exposed during the vulnerable period of the cell cycle. As would be predicted, the antimetabolite drugs are primarily active against rapidly dividing tumors such as acute leukemias and intermediate and high-grade lymphomas. High-dose regimens achieve a number of worthwhile objectives for these agents, including an enhancement of cross-membrane transport, saturation of anabolic pathways inside the cell, and prolongation of the period of effective drug concentration. However, achieving these objectives is realized at the cost of increased toxicity to normal proliferating marrow precursor cells and may produce significant and unexpected damage to normal organs, such as hepatic veno-occlusive disease (alkylating agents), cerebellar toxicity (cytosine arabinoside), or pulmonary toxicity (nitrosoureas and alkylating agents). Because hematopoietic stem cells can be harvested, stored, and reinfused, dose-limiting toxicities of high-dose chemotherapy are generally those affecting nonhematologic organs.
A number of other anticancer drugs do not require cells to be exposed during a specific phase of the cell cycle, although like the antimetabolites, these drugs are generally more effective against actively proliferating cells as compared to resting cells. These agents include the anthracyclines, the epipodophyllotoxins, and certain alkylating agents such as cyclophosphamide. Still others, most notably the nitrosoureas and busulfan, are equally toxic to dividing and nondividing cells and deplete marrow stem cells. In general, the duration of exposure to alkylating agents such as the nitrosoureas and cyclophosphamide is less important than the total dose of drug, while for the cell cycle–specific drugs (such as methotrexate and cytosine arabinoside), both drug concentration and duration of exposure determine cytocidal effect. For these agents, cytotoxicity is best related to the area under the plasma concentration-time curve of the drug. However, for drugs that act through alternate mechanisms, such as the taxanes, myelosuppression correlates best with the duration of exposure above a threshold plasma concentration, which is approximately 50 to 100 nM for paclitaxel and 200 nM for docetaxel.10
The choice of an appropriate dose and schedule of drug administration depends on a number of factors: (1) the drug’s cell cycle dependence, (2) its pattern of toxicity to marrow and other organs as a function of dose and schedule, (3) pharmacokinetic behavior, (4) potential interactions with other drugs, and (5) patient tolerance. The last factor will vary among individuals and will depend on physiologic parameters such as renal and hepatic functions (Table 16-1), which determine the patient’s ability to eliminate drug, and on the patient’s prior treatment experience, performance status, and age. Protocols for cancer chemotherapy must contain provisions for adjusting the dose or duration of drug infusion to accommodate these variables and should be followed diligently when employing those drugs.


Inadequate treatment of a sensitive tumor tends to select for the outgrowth of drug-resistant clones of the original tumor. It has been proposed that the basis for drug resistance is the spontaneous generation of resistant mutants, with subsequent selection of the drug-resistant mutant under the pressure of chemotherapeutic drugs.11 While formal proof of the clonal selection hypothesis is lacking, experimental models of drug resistance fit the hypothesis quite well, with the additional caveat that cancer drugs and irradiation are mutagenic themselves and increase significantly the rate at which drug-resistant mutants are generated. The hypothesis implies that the use of multiple drugs that do not share a common mechanism of resistance should be more effective than single agents; the hypothesis further suggests that multiple agents should be used simultaneously, since the likelihood of there being a doubly or triply resistant cell is the product of the probabilities of the independent drug-resistant mutations occurring at the same time in a single cell. The probability of a cell division resulting in mutation at any given genetic locus is approximately 10–6 for somatic cells; thus the probability of multiple independent mutations arising in the same cell will be 10–12 or lower. However, mutation rates may be distinctly higher in tumor cells and may be further increased by exposure to alkylating agents and irradiation.
In choosing drugs for combination therapy, one must bear in mind potential mechanisms of resistance. Classical MDR due to increased expression of drug efflux pumps such as the P-glycoprotein or the MRP proteins12,13 and 14 confers resistance to a broad spectrum of agents derived from natural products, including taxanes, anthracyclines, vinca alkaloids, and epipodophyllotoxins. Other mechanisms, such as dihydrofolate reductase amplification,15 are highly specific for a single drug, methotrexate. The common mechanisms are listed in Table 16-2. While none of these biochemical changes are routinely measured either prior to or following therapy, these mechanisms should be considered in developing new protocols and in choosing new therapy for patients who relapse from primary treatment.


In addition to drug-specific mechanisms of resistance, it is now recognized that mutations affecting recognition of DNA damage, such as the mismatch repair genes,16 lead to cisplatin, thiopurine, or alkylating agent resistance, while other mutations that block the induction of apoptosis, such as loss of p53,17 or overexpression of the antiapoptotic factors such as BCL-218 may render tumor cells insensitive to a broad array of drugs and modalities, including ionizing irradiation, alkylating agents, antimetabolites, and anthracyclines. Although the specific contribution of these factors to clinical resistance is still uncertain, emerging evidence suggests that mutations involving genes that control cell cycle and apoptosis, such as loss of p53 function, are strongly associated with clinically resistant and aggressive tumors17 and may be more relevant causes of drug resistance in the clinic than are the classical drug-specific mechanisms.
The folate antagonist aminopterin was shown by Farber and his associates to induce a complete remission in children with ALL.2 Unfortunately, these remissions were short-lived, and the leukemia invariably became resistant within months to further treatment. Subsequently, methotrexate supplanted aminopterin because it had a better therapeutic index. Methotrexate continues to be a key drug in maintenance therapy of ALL and in combination therapy of intermediate- and high-grade lymphomas. It is also used for treatment and prophylaxis of meningeal leukemia.
Methotrexate enters cells through an active uptake process mediated in most tumor cells by the reduced folate transporter,19 although a second transporter, the membrane folate binding protein,20 may contribute to the cellular uptake of other antifolates. Methotrexate inhibits the enzyme DHFR, which recycles oxidized folates to their active reduced state. Inhibition of DHFR leads to rapid depletion of intracellular folate coenzymes. Since folate coenzymes are required for thymidylate and purine biosynthesis, DNA synthesis is blocked and cell replication stops. Methotrexate is retained in certain cells for long periods of time as a consequence of an enzymatic process that adds up to five additional glutamate moieties to the g-carboxyl group of the drug (see Chap. 25). Polyglutamation may be an important determinant of methotrexate selectivity, since cells that effect this conversion efficiently, such as leukemic myeloblasts and lymphoblasts, are more susceptible to the drug than are normal myeloid precursors, which have limited capability for polyglutamation.21 Hyperdiploid lymphoblasts are particularly efficient in producing polyglutamated species and have a high cure rate with chemotherapy.22 Acquired resistance to methotrexate in patients with leukemia is due to increased levels of dihydrofolate reductase as a consequence of gene amplification,15 defective polyglutamation,23 and impaired drug uptake.19 Alterations of the DHFR enzyme leading to decreased binding of methotrexate have also been observed.24
Methotrexate is well absorbed when administered orally at low doses (5–10 mg/m2), but when doses exceed 30 mg/m2 absorption is progressively decreased and more variable. Therefore, doses greater than 25 mg/m2 should be administered parenterally. Poor absorption resulting in low blood levels of the drug (i.e., <16 µM) is associated with an increased risk of relapse in children with ALL receiving maintenance therapy with methotrexate.25
The concentration of methotrexate in plasma declines in a polyexponential manner. There is a very rapid initial disposition phase that persists for only a few minutes after intravenous administration. The intermediate disposition phase has a 2- to 3-h half-life and persists for 12 to 24 h after dosing. The terminal phase of drug decay is considerably slower, with an 8- to 10-h half-life. Methotrexate is primarily excreted unchanged by the kidney, although with large doses a minor fraction of the drug (7–30%) is inactivated by hepatic enzyme–mediated hydroxylation at the 7 position. Thus, patients with renal impairment should not be treated with methotrexate, since the prolonged exposure to high blood levels may result in life-threatening hematologic and gastrointestinal toxicity. When renal toxicity occurs following methotrexate treatment, large (100 mg/m2) and frequent (every 6 h) doses of leucovorin should be administered until the concentration of methotrexate in the blood decreases to nontoxic levels.26 High-dose methotrexate (>0.5 g/m2) together with leucovorin rescue is used to treat patients with high-grade lymphoma or ALL. This is usually accomplished by administering six to eight doses of 10 to 15 mg/m2 leucovorin at 6-h intervals, starting 6 to 24 h after the injection of methotrexate, and continuing until plasma concentrations of the drug fall below 1 µM. In patients receiving high-dose methotrexate, drug levels are routinely assayed 24 to 48 h after dosing to determine the rate of drug elimination and the safety for discontinuing leucovorin administration. In patients receiving such therapy, renal toxicity is generally the cause of decreased drug clearance, which may result from intrarenal precipitation of the parent drug or its 7-OH metabolite. Renal dysfunction can be prevented by alkalinizing the urine to pH 7.0 with intravenous sodium bicarbonate prior to and during therapy, or alternately, by intensive hydration. Both methotrexate and its hydroxylated metabolite are organic acids, which, like uric acid, are much more soluble in weakly alkaline urine. If drug concentrations in plasma exceed 1 µM during routine monitoring, leucovorin should be continued at doses of 50 to 100 mg/m2 every 6 h until methotrexate concentrations fall below 0.1 µM. In cases of extreme renal failure, with stable drug levels in the 10 µM range, leucovorin will not be effective and dialysis will not provide a sustained reduction in drug levels. The only effective measure in this circumstance is the administration of carboxypeptidase G, a bacterial enzyme that degrades antifolates.27 The enzyme can be obtained from the Cancer Therapy Evaluation Program of the National Cancer Institute and may be life saving.
The dose-limiting toxicities of methotrexate are myelosuppression and gastrointestinal toxicity. Toxic doses of methotrexate can induce thrombocytopenia and/or leukopenia, although leukopenia is more common. An early indication of methotrexate toxicity to the gastrointestinal tract is oral mucositis, while more severe toxicity may be manifested by diarrhea and gastrointestinal bleeding. Less common toxic effects of methotrexate are skin rash (10%), pneumonitis, and chemical hepatitis. The latter is reversible in most patients, but low- dose chronic administration may lead to fibrosis and cirrhosis of the liver in a small percentage of patients.
Methotrexate given intrathecally in doses of 12 mg every 4 days is used to treat meningeal leukemia and lymphoma. Toxicities due to this route of administration include acute arachnoiditis with nuchal rigidity and headache, as well as more chronic CNS toxicities, including dementia, motor deficits, seizures, and coma.28 Rarely these neurotoxicities develop hours after intrathecal drug administration, but more commonly they occur in the days or weeks after initiation of intrathecal treatment. Leucovorin is ineffective in reversing or preventing these toxicities. Patients exhibiting such signs should undergo evaluation to rule out progressive CNS leukemia or lymphoma, and if neither of these is present intrathecal cytosine arabinoside should be given instead of methotrexate.
Ara-C is an antimetabolite analog of cytidine differing in the configuration at the C2′ position of the sugar, with the C2′-hydroxyl group being cis-oriented relative to the C1′-N glycosyl bond, as opposed to the trans configuration of the ribose nucleoside. Ara-C is a mainstay in the induction of remission in patients with AML. When used with an anthracycline, remissions may be achieved in 60 to 80 percent of patients with this disease.
High doses (1–3 g/m2) of ara-C given at 12-h intervals for 6 to 12 doses are more effective alone or in a combination with anthracyclines than conventional doses (100–150 mg/m2 q 12 h) in consolidation therapy of AML, and they confer particular benefit in patients with cytogenetic abnormalities t(8:21), inv [16], t(9:16), and del (16) related to the core binding factor that regulates hematopoiesis.29 Ara-C has also been used to treat ALL, lymphoma, and both the chronic and the blast phases of CML, but its exact role in the treatment of these malignancies is less well defined.
Ara-C is converted to the nucleoside triphosphate (ara-CTP) intracellularly. Ara-CTP is an inhibitor of DNA polymerase and is also incorporated into DNA, where it terminates strand elongation.30 Ara-C and its mononucleotide are inactivated by two intracellular enzymes, cytidine deaminase and deoxycytidylate deaminase respectively. The ara-U formed as a consequence of ara-C deamination is more slowly cleared from plasma than is ara-C and may inhibit subsequent inactivation of ara-C in high-dose regimens.
Acquired ara-C resistance in experimental leukemias consistently results from the loss of deoxycytidine kinase, the initial activating enzyme in the ara-C pathway.31 Other changes implicated in experimental tumors include decreased drug uptake, increased deamination, increased pool size of competitive deoxycytidine triphosphate, and inhibition of the apoptotic pathway. Some of these changes have been reported in studies of human leukemia, but these results have not been confirmed in definitive trials.18,31,32
Ara-C is administered intravenously either as a bolus injection or continuous infusion. It is not orally bioavailable due to degradation by cytidine deaminase present in the gastrointestinal epithelium and liver. Ara-C distributes rapidly throughout total body water and is eliminated from plasma with a biological half-life of 7 to 20 min. Most of the dose is excreted as ara-U, an inactive metabolite, which is formed in plasma, the liver, granulocytes, and other tissues. Product inhibition of ara-C deamination by ara-U is believed to be responsible for the prolongation of the biological half-life of the drug as larger doses are administered.33 Single bolus injections and short infusions (0.5- to 1-h duration) at doses as high as 5 g/m2 produce little myelotoxicity because of the drug’s rapid clearance, whereas continuous intravenous infusion of only 1g/m2 over 48 h produces severe marrow toxicity. Unlike most drugs, a relatively high concentration of ara-C is achieved in the cerebrospinal fluid after intravenous administration, which may approach 50 percent of the corresponding concentration in plasma.
Ara-C is also used intrathecally to treat meningeal leukemia. Doses of 70 mg in adults are usually employed and afford cerebrospinal fluid levels of the drug near 1.0 mM, which decline with a half-life of 2 h. Ara-C has been impregnated into a gel matrix for sustained release into the cerebrospinal fluid, thus avoiding the need for repeated spinal taps. Initial clinical results in spinal lymphomatous meningitis resistant to methotrexate is promising.34
The dose-limiting toxicity for conventional dosing regimens of ara-C, 100 to 150 mg/m2 per day for 5 to 10 days, is myelosuppression. Some nausea and vomiting also occur at these doses, the severity of which increases markedly when higher doses are employed, although repeated administration of the drug results in some tolerance. The nadir of the white count and platelet count occurs at about day 7 to 10 after the last dose of drug. Neurologic, gastrointestinal, and liver toxicity have also been observed when high-dose regimens are used. Hepatotoxicity ranges from abnormalities in serum transaminase levels to frank jaundice. The severity of these effects increases as the duration of therapy is prolonged; however, toxic effects rapidly subside upon discontinuation of treatment. Pulmonary infiltrates due to noncardiogenic pulmonary edema are frequently observed in leukemic patients receiving ara-C, as are gastrointestinal ulcerations with bleeding and infrequently perforation. Ara-C treatment is also reported to predispose to Streptococcus viridans pneumonia.35
In patients over 50 years of age, high-dose ara-C (3 g/m2 q12 h) causes cerebellar toxicity, manifested as ataxia and slurred speech.36 Confusion and dementia may supervene, leading to a fatal outcome. Cerebellar toxicity is more frequent in patients with abnormal renal function, despite the fact that the drug is primarily eliminated by metabolism, not by renal excretion, and is thought to result from slowed elimination of ara-U, with consequent inhibition of ara-C deamination. Intrathecal ara-C is usually well tolerated, but neurologic side effects have been reported (seizures, alterations in mental status).
The only riboside nucleoside to attract clinical interest, 5-azacytidine, exhibits cytotoxic activity and also induces differentiation of malignant cells at low doses. The latter action is believed to result from an inhibition of methylation of cytosine bases in DNA, leading to enhanced transcription of otherwise silent genes. The differentiating effects of 5-azacytidine are the basis for its experimental use in the induction of fetal hemoglobin synthesis in patients with sickle cell anemia and thalassemia37 and in low-dose therapy of myelodysplastic syndromes. The usual doses administered are 150 to 200 mg/m2 per day for 5 days.
5-Azacytidine is rapidly deaminated, affording a chemically unstable metabolite which immediately degrades into inactive products.38 Pharmacologic activity results from phosphorylation of the parent compound by cytidine kinase, with subsequent conversion to a triphosphate nucleotide that becomes incorporated into RNA and DNA. The precise mechanism of cytotoxicity has not been defined. The primary clinical toxicities include reversible myelosuppression, rather severe nausea and vomiting, hepatic dysfunction, myalgias, and fever and rash.
Purine analogs have won an important role in remission induction and maintenance for ALL, and in the past decade new analogs have shown remarkable activity in chronic leukemias and small cell lymphomas. With methotrexate, 6-mercaptopurine (6-MP) is a critical component in the maintenance phase of curative therapy of childhood ALL. Other clinically useful purine analogs include azathioprine, a 6-MP precursor and potent immunosuppressive agent; allopurinol, an inhibitor of xanthine oxidase, useful in the prevention of uric acid nephropathy; 2-chlorodeoxyadenosine, effective in the treatment of hairy cell leukemia and other lymphoid malignancies; 6-thioguanine (6-TG), an antileukemic agent; fludarabine-phosphate (2-fluoro-ara-adenosine monophosphate), an effective agent for chronic lymphocytic leukemia; and antiviral compounds such as ara-A (vidarabine). Deoxycoformycin, a potent inhibitor of adenosine deaminase, is effective in the treatment of T-cell malignancies and hairy cell leukemia.
Both 6-MP and 6-TG have a thiol group substituted for the 6-oxo or 6-hydroxy group of hypoxanthine or guanine, respectively. Both compounds are converted to nucleotides by the enzyme HPRT. The exact mechanism whereby these analogs exert their cytotoxic effects is not known.39 De novo purine synthesis is blocked by the 6-TG nucleotide, as is the conversion of inosine monophosphate to adenosine and guanosine monophosphates.40 The nucleotides of both 6-MP and 6-TG are incorporated into DNA. Thiopurines incorporated into DNA are recognized by the mismatch repair system, triggering apoptosis.16 Cell death correlates with the extent of their incorporation into DNA.
In experimental tumor cells, resistance is most commonly due to decreased activity of HPRT.41 In human ALL, resistance has also been ascribed to an increase in activity of membrane alkaline phosphatase capable of degrading the nucleotides.42 Absence of HPRT activity is an uncommon cause of resistance in human AML; an alteration of this enzyme leading to decreased thiopurine binding is present in the blast cells of some patients. Resistance may also be mediated by methylation of the thiol group by 5-thiopurine methyl transferase.40,43 Low levels of red blood cell thiopurine nucleotides correlate with a high risk of clinical relapse in patients with ALL.44
Methotrexate and 6-MP are highly synergistic, possibly because methotrexate blocks the de novo synthesis of purines and enhances the utilization of preformed purines and purine analogs such as 6-MP.
Both 6-TG and 6-MP are given orally at doses of 50 to 100 mg/m2 per day. Oral absorption of 6-MP is erratic, as only 16 to 50 percent of an oral dose is systemically available.45 Food and antibiotics may decrease absorption. 6-MP is inactivated by metabolism to 6-thiouric acid, a reaction catalyzed by xanthine oxidase. Allopurinol inhibits the metabolism of 6-MP but not of 6-TG. Therefore, it is generally recommended that dosages of 6-MP must be reduced by 75 percent in patients receiving allopurinol. 6-TG is inactivated primarily by S- methylation, followed by oxidation and desulfuration. Dose reduction is not necessary when 6-TG and allopurinol are administered together.
The two drugs, 6-TG and 6-MP, are equally myelotoxic, with marrow toxicity following the pattern typical of cytotoxic drugs, producing nadirs of white blood cells and platelets at 7 to 10 days after treat ment. Moderate nausea and vomiting may also be observed. Mild but rapidly reversible hepatotoxicity may be experienced by patients after treatment with either compound. Cirrhosis has occurred in some children with leukemia receiving long-term therapy with 6-MP. Thiopurine methyl transferase, which inactivates 6-thiopurines, occurs in several polymorphic forms that fail to metabolize the analogs. About 10 percent of the Caucasian population are heterozygous for ineffective polymorphic forms of the enzyme and have increased sensitivity to thiopurines, while 1 in 300 patients is homozygous for the inactive forms and at risk for overwhelming toxicity. Thiopurine nucleotide levels in lymphoblasts and in red cells are inversely related to enzyme activity.46
Originally synthesized as a deamination-resistant analog of adenosine, fludarabine phosphate has outstanding activity in CLL.47 It is strongly immunosuppressive, like the other purine analogs, and has potential use in nonmyeloablative allogeneic bone marrow transplantation48 and in the treatment of collagen vascular diseases.
The pharmacology of fludarabine requires dephosphorylation to allow cellular uptake, and then intracellular phosphorylation. Fludarabine phosphate undergoes rapid dephosphorylation in plasma to the nucleoside fludarabine, which readily enters cells, and is restored intracellularly to the monophosphate level by deoxycytidine kinase. The triphosphate inhibits DNA polymerase and becomes incorporated into DNA and into RNA.49 Its mechanism of cytotoxicity is believed to result from DNA chain termination and induction of apoptosis.50,51
The drug is available in the United States as an intravenous preparation, although in Europe it can be given orally. It has 60 to 80 percent bioavailability. Because it is resistant to adenosine deaminase, fludarabine is eliminated primarily by renal excretion, although specific guidelines for dose reduction in patients with compromised renal function have not been established. In CLL, the recommended doses are 20 to 30 mg/m2 per day for 5 days given as 2-h infusions and repeated every 4 weeks. When administered at these doses, fludarabine causes only moderate myelosuppression. In CLL patients its antileukemic effect will lead to a progressive but relatively slow improvement in marrow function over a period of 2 to 3 cycles of treatment, with a median time to disease progression of 31 months.47 However, the drug also exerts cytotoxic effects against both B and T lymphocytes, lowering CD4 T-cell counts to 150 to 200 cells per mm3 and predisposing patients to opportunistic infection. In patients with a large tumor burden, rapid tumor lysis may rarely lead to hyperuricemia, renal failure, and hypocalcemia (tumor lysis syndrome).52 Thus, patients should be well hydrated and their urine alkalinized prior to beginning therapy. Peripheral sensory and motor neuropathy may occur during standard-dose therapy; and rare episodes of hemolytic anemia with both warm and cold antibodies have been reported.53 At higher doses (125 mg/m2 per day for 5 days) altered mental status, seizures, coma, and optic neuritis have been reported.
The extreme sensitivity of normal and malignant lymphocytes to deamination-resistant purine analogs is further exemplified by the potent activity of 2-CdA in hairy cell leukemia, chronic lymphocytic leukemia, and low-grade lymphomas.54,55 A single course of 2-CdA, typically 0.09 mg/kg per day for 7 days by continuous intravenous infusion, induces complete response in 80 percent of patients with hairy cell leukemia, with partial responses in the remainder. Administration by subcutaneous injection or by 2-h intravenous infusions for 5 days to the same total dose achieves similar results. The drug has much the same intracellular fate as fludarabine, undergoing phosphorylation by deoxycytidine kinase and further conversion to a triphosphate that becomes incorporated into DNA. The triphosphate of 2-CdA has a very long intracellular half-life of 9.7 h in CLL cells isolated from patients treated with the drug.56 The triphosphate also accumulates in mitochondria, disrupting oxidative phosphorylation, and inhibits ribonucleotide reductase and depletes NAD levels in tumor cells. All of these actions might help explain the drug’s toxicity to slowly dividing lymphoid malignancies such as hairy cell leukemia and CLL. The actual mechanisms by which 2-CdA induces DNA strand breaks are not completely understood. However, similar to fludarabine, it inhibits DNA chain extension and daughter strand synthesis.57 Furthermore, the drug induces apoptosis (programmed cell death) in some cell lines.58
2-CdA is eliminated primarily by renal excretion, with a terminal plasma half-life of 21 h. 2-CdA retains effectiveness in at least a fraction of hairy cell leukemia patients resistant to deoxycoformycin or fludarabine, although clinical experience with sequential use of these drugs is limited. Toxicities of 2-CdA include transient myelosuppression, fever, and occasional infections possibly related to immunosuppression. The development of cumulative thrombocytopenia during treatment with repeated courses of the drug may limit its use.
DCF contains a unique 7-carbon primary ring system that closely resembles the transition-state intermediate of the adenosine deaminase reaction. As such, DCF is a potent inhibitor of the enzyme, leading to accumulation of intracellular adenosine and deoxyadenosine nucleotides.59 In addition, the triphosphate of DCF is incorporated into DNA. The imbalance in purine nucleotide pools produced by DCF probably accounts for its cytotoxicity.
Although initial trials of DCF demonstrated striking renal and neurologic toxicities at doses of 10 mg/m2 per day or greater, lower doses (4 mg/m2 biweekly) have proven to be extremely effective in inducing pathologically confirmed complete responses in hairy cell leukemia. At this lower dose, severe depletion of normal T cells occurs and may predispose to opportunistic infection.60 The optimal dose may be lower than 4 mg/m2 biweekly. The drug is eliminated entirely by renal excretion, necessitating proportional dose reduction in patients with reduced creatinine clearance.
Hydroxyurea inhibits ribonucleotide reductase, the enzyme that converts ribonucleotide diphosphates to deoxyribonucleotides. Hydroxyurea is most commonly used in the treatment of polycythemia vera and the chronic phase of CML and to lower the leukocyte count rapidly during blast crisis of CML. Resistance to hydroxyurea occurs in experimental tumors as a consequence of an increase in ribonucleotide reductase activity, or through mutations that produce an enzyme that binds the drug with decreased affinity.
Hydroxyurea is usually administered orally and is well absorbed, even when large doses such as 50 to 75 mg/kg are given. Peak plasma levels following oral administration are achieved at about 1 h and decline rapidly thereafter. Renal excretion is the major route of drug elimination.
The major toxicities of hydroxyurea are leukopenia and the induction of megaloblastic changes. Except for nausea, little other toxicity has been observed with this drug, even when large doses are administered. Hydroxyurea, like cytosine arabinoside, is an S phase–specific agent. Accordingly, single large doses effect little toxicity other than myelosuppression. The nadir of the leukocyte count occurs 6 to 7 days after a single dose of drug, and the leukocyte count recovers rapidly. When hydroxyurea is used as therapy for essential thrombocythemia, there may be an increase in the incidence of acute myelogenous leukemia.134 The agent is also used in nonmalignant disorders, notably sickle cell anemia (see Chap. 47).
Among the three vinca alkaloids that have been extensively evaluated during the past three decades—vinblastine, vincristine, and vindesine—only the first two are now available commercially in the United States. Both of these drugs are used widely in the treatment of hematologic neoplasms; vinblastine because of its excellent activity in the treatment of Hodgkin disease and testicular cancer, and vincristine in lymphomas, breast cancer and childhood leukemia, and other solid tumors. Another drug belonging to this class of compounds, Navelbine, is used primarily for the treatment of breast and lung cancers.
The vinca alkaloids exert their cytotoxic action by binding to tubulin, a protein found in the cytoplasm of cells. Microtubules, assembled through polymerization of tubulin dimers, form the spindle along which the chromosomes migrate during mitosis and maintain cell structure. Binding of the vinca alkaloids to tubulin leads to inhibition of the process of assembly of the mitotic spindle,61 arresting cells in metaphase and inducing apoptosis. Resistance to the vinca alkaloids may be acquired through the development of the MDR phenotype,12 which causes increased efflux of the drugs from the resistant cells. Alternatively, resistant cells may contain mutant tubulin with decreased avidity of vinca binding.62 The clinical significance of these resistance mechanisms, however, is still unproven.
Vincristine and vinblastine are both administered by the intravenous route. The average single dose of vincristine is 1.4 mg/m2 and that of vinblastine 8 to 9 mg/m2. Sequential doses of the drugs are usually given at 2- to 4-week intervals. These doses provide peak plasma drug concentrations of approximately 1 µM. The plasma concentration–time profile of vincristine is characterized by a very rapid initial disposition phase followed by two slower phases of decay, with half- lives of 3 h and 23 to 85 h. In comparison, the intermediate and terminal disposition phases of vinblastine have half-lives of 1 h and 20 h respectively. Almost 70 percent of a dose of vincristine is metabolized by the liver and excreted in the feces. Metabolism is also the major route of inactivation of vinblastine, but details are lacking with respect to the site of metabolism and the identity of metabolic products. Accordingly, the dose of vincristine or vinblastine should be reduced in patients with hepatic impairment. While specific guidelines for dose reduction have not been completely developed, a 50 percent decrease in dose is recommended for patients presenting with a bilirubin greater than 3 mg/dL. Dose reduction is not necessary for patients with impaired renal function, as very little intact drug is excreted in urine.
The dose-limiting side effect of vincristine is neurotoxicity, which usually occurs when the total dose received exceeds 6 mg/m2. The initial signs of neurotoxicity are paresthesia of the fingers and lower extremities and loss of deep-tendon reflexes. Continued administration may lead to profound loss of motor strength, such as weakness of dorsiflexion of the foot and extension of the wrists. Elderly patients are particularly susceptible to such toxicities. Occasionally cranial nerve palsies may lead to vocal chord paralysis or diplopia, and severe jaw pain may result from vincristine administration. At high doses of vincristine (>3 mg total single dose), autonomic neuropathy may cause obstipation and paralytic ileus. Sensory changes and reflex abnormalities slowly improve when the drug is discontinued; however, motor impairment improves less rapidly and may be irreversible. Inappropriate ADH release, resulting in symptomatic dilutional hyponatremia is sometimes observed.
While marrow suppression is not common with vincristine administration, some marrow toxicity may be noted in patients with impaired marrow function as a consequence of prior treatment with other drugs. The primary toxicity of vinblastine is leukopenia. The white count reaches a nadir at day 7 and reverses rapidly thereafter. Mucositis may result from higher doses (>8 mg/m2) of vinblastine or when it is used in combination with other cytotoxic drugs. Neurotoxicity is rare, but ileus may occur at high doses.
Both drugs cause severe pain and local toxicity if extravasated. Neither drug should be given intrathecally, since deaths have been reported from vincristine administered inadvertently into the cerebrospinal fluid.
The newest of the antimitotic drugs are the taxanes, paclitaxel (Taxol) and docetaxel (Taxotere). Paclitaxel was purified from an extract of the bark of Taxus brevifolia, while docetaxel is a closely related semisynthetic derivative. Neither drug has won an important role in the treatment of hematological malignancies, although paclitaxel has modest activity in the lymphomas.63 Taxanes are highly active in a number of solid tumors, including breast, ovarian, and lung cancers. They bind to the b-tubulin subunit of microtubules and promote the polymerization of microtubules, leading to disordered mitotic spindle formation and a block in the progression through mitosis.64 Both drugs induce apoptosis in tumor cells irrespective of p53 status of the cells and kill cells at 1 to 10 nM concentrations in cell culture in a time-dependent manner.65,66 The taxanes are subject to MDR mediated by the mdr and mrp genes, and also b-tubulin mutations. Because they are highly insoluble in aqueous solution, both drugs are formulated in lipid-based solvents that cause occasional hypersensitivity reactions. Thus, paclitaxel is given after pretreatment with antihistamines (cimetidine and Benadryl) and Decadron. Both drugs are cleared primarily by hepatic CYP metabolism, with terminal plasma half-lives of 10 to 13 h. Their metabolism is stimulated by Dilantin and other CYP-inducing drugs and inhibited by CYP substrates such as ketoconazole. Their major toxicities, aside from hypersensitivity, are a sharp but brief leukopenia, milder thrombocytopenia, and mucositis. High-dose or repeated cycles of the taxanes cause a sensory and motor peripheral neuropathy that is reversible with drug discontinuation. Occasional patients have experienced atrial conduction block or atrial or ventricular arrhythmias after paclitaxel administration, and the combination of paclitaxel with doxorubicin may produce a greater incidence of congestive heart failure than seen with doxorubicin alone.67 A syndrome of progressive fluid retention and peripheral edema occurs in patients receiving multiple cycles of docetaxel and can be at least partially prevented by pretreatment with corticosteroids.68
This group of compounds includes synthetic derivatives of 20 (S)-camptothecin, a naturally occurring compound initially isolated from the Camptotheca accuminata bush. The campothecins interact with a unique target, topoisomerase I, stabilizing the enzyme’s complex with DNA and preventing the resealing of DNA single-strand breaks induced by the enzyme. Resistance arises through mutation, deletion, or decreased expression of the topoisomerase I gene. The primary agents in clinical use are irinotecan, which is approved for treatment of colon cancer, and topotecan, approved for use against ovarian cancer and small cell lung cancer. Irinotecan, most commonly administered intravenously at a dose of 125 mg/m2, once each week for 4 weeks every 42 days, has shown promise against lymphomas in phase II trials, but has received limited evaluation in the United States for this indication.69 In contrast, topotecan has impressive remission-inducing activity in patients with myelodysplasia and chronic myelomonocytic leukemia, both as a single agent (1.5 mg/m2/day for 5 days) and in combination with ara-C.70 The two drugs differ substantially in their profile of toxicities and pharmacokinetic behavior. Irinotecan is a water-soluble prodrug which affords the active species, SN-38, by carboxyl esterase–mediated cleavage of the basic promoiety. SN-38 and its parent drug are eliminated by biliary excretion, either directly as in the case of the parent drug or upon glucuronidation of the active metabolite SN-38. Therefore, irinotecan must be used with caution and at lower doses in patients with Gilbert disease or hepatic dysfunction.71 Approximately two-thirds of the dose of topotecan is eliminated by renal excretion, with the remainder being cleared by biliary excretion. Dose adjustment proportional to creatinine clearance is indicated in patients with renal failure.72 Topotecan toxicity consists mainly of myelosuppression, and to a lesser degree mucositis, while irinotecan causes a profound diarrhea that is responsive to loperamide, and a more modest myelosuppression.
The anthracyclines in general clinical use are doxorubicin, daunorubicin, and idarubicin, and in Europe, epirubicin. Mitoxantrone (Novantrone), a closely related anthracenedione, has very similar pharmacologic properties. The anthracyclines are produced by a Streptomyces species, while mitoxantrone is a synthetic compound not containing a sugar moiety. Doxorubicin (Adriamycin) has a broad spectrum of activity against neoplastic disease; it is an important drug in the treatment of hematologic malignancies, especially Hodgkin disease and the other lymphomas. Daunorubicin (daunomycin) and idarubicin are used almost exclusively in combination with ara-C for the treatment of AML. Mitoxantrone is employed for the treatment of AML and breast cancer.
These drugs exert their effects by forming a complex with DNA and topoisomerase II, leading to double-stranded DNA strand breaks. The various anthracycline analogs differ in their specificity for binding to DNA base sequences.73 To varying degrees they also generate free radicals through oxidation-reduction cycling of their quinone groups, an action that may contribute to their cardiac toxicity. The anthracyclines enter cells through a passive transport process and are pumped out by both the MRP protein and the P-glycoprotein transport system.12 Other mechanisms for anthracycline resistance include decreased or altered topoisomerase II activity.
Doxorubicin and daunorubicin are converted to active hydroxyl metabolites, and thereafter to a spectrum of inactive products in the liver. Only a minor fraction of the dose is excreted in the urine as the parent drug or active metabolite. The pharmacokinetics of the clinically useful anthracyclines are predominantly influenced by their terminal disposition phases, which exceed 10 h. While prolongation of the half-life of doxorubicin has been reported in studies of patients with compromised liver function, no clear correlations with toxicity have been established. Idarubicin is the only anthracycline that exhibits reasonable oral bioavailability, being 20 percent for the parent drug and 40 percent for parent plus idarubicinol, the primary active metabolite.74 Idarubicinol has a very prolonged biological half-life, ranging from 50 to 60 h, and is likely responsible for the antitumor activity of this drug. In contrast to doxorubicin and daunorubicin, it is eliminated significantly by renal excretion. Mitoxantrone has a brief initial plasma half-life of 1.1 h and a considerably longer terminal half-life of 23 to 42 h. Only a minor fraction of unchanged drug is excreted in the urine (<10%) or stool (<20%). The majority of the drug is probably metabolized or bound to tissues. Patients with impaired hepatic function may have a more prolonged elimination of mitoxantrone.
The usual dose of doxorubicin when administered as a single agent by bolus intravenous injection is 60 to 75 mg/m2 every 3 to 4 weeks. Less cardiac toxicity may result from schedules that avoid high peak plasma concentrations, such as weekly doses (15–25 mg/m2) or continuous intravenous infusion over 48 to 96 h. When given in combination with other myelotoxic agents such as cyclophosphamide, the dose of doxorubicin is usually decreased by one-third to one-half. Although daunorubicin has been used as the anthracycline of choice in the treatment of AML, usually in combination with ara-C, doxorubicin and mitoxantrone and idarubicin may be equally effective.
Myelosuppression is the primary toxicity of this class of drugs, with a nadir occurring 7 to 10 days after single-dose administration and recovery by 2 weeks. Mitoxantrone produces less nausea and vomiting than does daunorubicin or doxorubicin. Doxorubicin may cause mucositis, especially when used in maximally tolerated divided doses given over 2 to 3 days or when used in combination with other drugs that cause mucositis. These drugs may also cause a reaction in previously irradiated tissues, especially when the drug is administered just prior to or in the weeks following irradiation. Alopecia often occurs. Extravasation of these drugs results in tissue necrosis.
Cardiac toxicity is a major toxic effect of doxorubicin and daunorubicin.75 Cardiac toxicity appears to be mediated by free radical formation catalyzed by the quinone function of the anthracycline nucleus and can be averted by free radical–scavenging agents (sulfhydryl compounds) or by iron chelators such as dexrazoxane (ICRF-187).76 It is not known whether these modulators affect antitumor activity. Both acute effects, manifested by arrhythmias and conduction abnormalities and a “pericarditis-myocarditis syndrome,” and chronic congestive heart failure may occur. Ejection fraction measurements have been helpful as a noninvasive technique to demonstrate a decline in myocardial function and a rising risk of myocardial failure with increasing doses. Anthracycline therapy should be discontinued when the ejection fraction falls below 40 percent. Most patients will tolerate total doses of 450 to 550 mg/m2 doxorubicin or daunorubicin before the risk of cardiac damage exceeds 5 percent.77 There is a high risk of cardiac damage at lower cumulative doses in patients receiving mantle irradiation. Once clinically overt cardiac toxicity occurs, usually manifested by congestive heart failure, the mortality rate is high. Congestive heart failure usually occurs during therapy or less than 1 month following cessation of treatment; rarely, heart failure may occur many months later or may be elicited by a second drug, such as mitoxantrone or mitomycin C. Children treated with anthracyclines may show abnormal cardiac development and late congestive heart failure in their teenage years.78 Those who receive greater than 300 mg/m2 demonstrate decreased myocardial contractility and increased ventricular dimension when tested years later,79 thus leading to the recommendation that total anthracycline dose be limited to no more than 300 mg/m2 in children. Low-dose schedules cause less cardiac toxicity. Treatment with idarubicin or mitoxantrone is associated with a lower risk of cardiac toxicity, but the data are less complete for these newer agents.
Two semisynthetic derivatives of podophyllotoxin, VP-16 (etoposide) and VM-26 (teniposide), have significant clinical activity in hematologic malignancies. Etoposide has been incorporated into combination therapy regimens for Hodgkin disease, diffuse aggressive lymphomas, and leukemias and is frequently used as a component of high-dose chemotherapy regimens. Teniposide has been used investigationally to treat various forms of childhood acute leukemia and appears to be synergistic with ara-C.80
These compounds induce double-stranded breaks in DNA through their sequence-specific binding to DNA in complex with topoisomerase II, a DNA repair enzyme.81 One mechanism of resistance is increased expression of the MDR phenotype (12). A second mechanism results from decreased topoisomerase II activity or mutation of the enzyme, resulting in decreased drug binding.82,83
Etoposide has excellent oral bioavailability and may be administered either orally or intravenously. The usual intravenous dose schedule used for etoposide is 100 to 120 mg/m2 per day for 3 days, either consecutively or every other day. When administered orally, the dose should be increased twofold over the intravenous dose, since 50 to 67 percent of the dose is absorbed. Approximately 30 to 40 percent of an intravenous dose of etoposide is excreted intact in the urine; thus, doses of etoposide require modification for patients with compromised renal function but not hepatic dysfunction.84 The biological half-life of etoposide is 15 h. The clinical activity of etoposide is highly schedule dependent. Single conventional doses are essentially without antitumor effect as compared to consecutive daily doses for 3 to 5 days. The oral administration of 50 mg per day for 2 to 3 weeks is a commonly used regimen that takes advantage of that schedule dependency.
The pharmacokinetics of teniposide are very similar to those of etoposide, with a terminal plasma half-life of 20 to 48 h. However, little parent drug appears intact in the urine, and dose modification for patients with renal dysfunction is unnecessary.
When administered intravenously, both etoposide and teniposide should be infused over a 30-min period to avoid hypotensive episodes. The major toxicity of both drugs is leukopenia, which is rapidly reversible. Thrombocytopenia is less common. Nausea and vomiting often follow etoposide administration. Alopecia may occur with both drugs. Other toxicities, such as fever, mild elevation of liver function tests, or peripheral neuropathy, are relatively uncommon. Because the major toxicity of etoposide is limited to the marrow, this drug is under intensive investigation as a component of high-dose regimens followed by marrow transplantation. In high-dose etoposide protocols (3 to 4 g/m2 given over 3 to 5 days) oropharyngeal mucositis becomes a prominent toxicity. Less frequent high-dose toxicities include hepatocellular damage and rarely anaphylactic-like symptoms, probably related to the Cremophor-based vehicle. Reports of secondary acute myeloid leukemia following etoposide treatment in children with ALL85 and in adults with testicular cancer have alerted clinicians to this potential complication.86
Bleomycin is a mixture of peptides produced by the fungus Streptomyces verticillis.87 Because it has antitumor effects with little or no marrow toxicity, it is commonly used as part of combination regimens (ABVD) to treat Hodgkin disease, the aggressive lymphomas, and germ cell tumors. Bleomycin acts by causing both single- and double-strand breaks in DNA. These breaks form as a consequence of a bleomycin:Fe(II) complex with DNA leading to proton abstraction from the deoxyribose and cleavage at the 4′-carbon.88,89 and 90 In experimental tumors, resistance to bleomycin has been attributed to increased concentrations of an aminohydrolase that cleaves and inactivates the drug.91 Some resistant cell lines exhibit enhanced capacity to repair strand breaks, and in others resistance results from decreased drug accumulation. Additional factors, such as increased free radical detoxification may also influence toxicity. The tumor specificity of this drug and the lack of toxicity of bleomycin to marrow and the gastrointestinal tract may be due to different levels of a bleomycin-inactivating enzyme in these tissues. The aminohydrolase is found in low concentrations in the lung and skin, a possible explanation for the susceptibility of these two normal organs to damage by this drug. Cell killing occurs throughout the cell cycle.
Bleomycin may be administered intravenously or intramuscularly for systemic therapy, as well as intrapleurally or intraperitoneally for control of malignant effusions. The half-life of drug elimination from plasma has been estimated to be 2 to 3 h. After a single intravenous injection, over half the dose is excreted in the urine during 24 h.92 Bleomycin elimination may be markedly impaired in patients with poor renal function; such patients are at risk of overwhelming skin and lung toxicity. Dose reduction proportional to creatinine clearance should be considered in these patients.
Bleomycin has few or no effects on normal marrow; however, in patients given other myelosuppressive drugs or recovering from marrow toxicity from these agents, additional mild myelosuppression may be observed. The primary toxicities that result from bleomycin are pulmonary fibrosis and skin changes. In experimental settings, the drug induces the secretion of numerous cytokines, including IL-6 and TGB-b, by alveolar macrophages, leading to collagen deposition.93 The risk of pulmonary toxicity is related to the cumulative dose administered, increasing to 10 percent in patients given more than 450 mg.94 Risk is also greater in patients over the age of 70, in patients with underlying lung disease, in patients receiving bleomycin who are given high oxygen concentrations, or in patients who have had previous radiotherapy to the lungs. Single doses of 25 mg/m2 or more are more likely to predispose to this toxic effect. Symptoms of pulmonary toxicity include cough and dyspnea. Chest x-rays show nonspecific infiltrates, especially in the lower lobes. Open lung biopsy may be required to distinguish bleomycin pulmonary toxicity from infection or malignant disease. Findings of bleomycin toxicity include an inflammatory alveolar infiltrate with edema, pulmonary hyaline formation, and squamous metaplasia of the alveolar lining cells. These changes progress to intraalveolar and interstitial fibrosis over a period of months. Patients with bleomycin lung toxicity have a defect in carbon monoxide diffusing capacity, a test of possible value in predicting potential pulmonary toxicity.95 Since there is no specific therapy for patients with bleomycin lung toxicity, close attention should be paid to early pulmonary symptoms and radiographic changes. In patients with bleomycin pulmonary toxicity, some improvement may be seen on discontinuation of the drug, but the pulmonary fibrosis is usually not reversible. Glucocorticoids are of no proven benefit once fibrosis has occurred.
The dermatological toxicity of bleomycin is also dose related. Erythema, hyperpigmentation, hyperkeratosis, and even ulceration may occur when the drug is given in conventional daily doses for longer than 2 to 3 weeks. Areas of skin pressure, especially of the hands, fingers, and joints, are initially affected. Nail changes and alopecia may also occur with continued use of the drug. In combination regimens (e.g., ABVD) where bleomycin is used intermittently, skin toxicity usually does not occur.
Fever and malaise are common symptoms and may be alleviated with the use of acetaminophen. Hypersensitivity reactions have also been observed. Idiosyncratic cardiovascular collapse has been rarely noted. A 1-mg or 2-mg test dose administered to such susceptible patients may result in hypotension, tachycardia, pulmonary insufficiency, or anaphylactoid reactions within 30 to 60 min. Their occurrence precludes further treatment with bleomycin.
The enzyme L-asparaginase is used clinically in the treatment of lymphoid malignancies, in particular in poor-risk B-cell ALL, T-cell ALL, and the lymphomas.
The cells causing these lymphoid malignancies require exogenous L-asparagine for growth, and they obtain this amino acid from the circulating pool of amino acids generated primarily by the liver. The enzyme L-asparaginase, which catalyzes the hydrolysis of asparagine to aspartic acid and ammonia, is capable of rapidly depleting the serum level of L-asparagine. This induces an asparagine deficiency in lymphoid malignant cells. Resistant tumors are able to respond by rapid induction of asparagine synthetase.96 Resistance can be detected by in vitro incubation of leukemic cells with asparaginase.97
Three preparations of L-asparaginase are available for clinical use in the United States. The product purified from Escherichia coli is employed as a first-line agent, while a second preparation (pegaspargase), derived by attachment of polyethylene glycol to the E. coli enzyme, is primarily reserved for patients with hypersensitivity to the unmodified enzyme and has a longer half-life. A third preparation, purified from Erwinia chrysanthemi, can be obtained from the National Cancer Institute of the United States for patients hypersensitive to the E. coli enzyme. The enzyme from E. coli is primarily used in the clinical treatment of ALL and high-grade lymphomas. The various preparations differ in their pharmacokinetics and recommended doses.98,99
L-Asparaginase is administered either intravenously or intramuscularly. Dose schedules commonly used are 6000 IU/m2, or in European trials, 5000 to 10,000 IU/m2 every third day for 3 to 4 weeks for the unmodified enzyme and 2500 IU every 2 weeks for the pegaspargase.99,100 Blood levels of L-asparaginase are detectable for at least three days after a single dose is administered intravenously or intramuscularly. Blood and cerebrospinal fluid concentrations of L-asparagine fall below 1 µM within minutes after enzyme injection and begin to be measurable again 7 to 10 days after a single dose. The half-life of the unmodified E. coli enzyme in plasma is 14 to 24 h, while that of pegaspargase is fivefold to tenfold longer.
Reactions to the first dose are uncommon, but after two or more doses of the drug, hypersensitivity may develop, varying from urticarial reactions to hypotension, laryngospasm, and cardiac arrest. Skin testing to predict allergic reactions is helpful in some but not all cases and should be performed to confirm a clinical suspicion of hypersensitivity. Hypersensitive patients may have antibodies to L-asparaginase in their plasma. However, more than half the patients with such circulating antibodies will not display an overt allergic reaction to the drug,100 but they may have more rapid disappearance of drug from plasma and an inadequate clearance of asparagine from plasma and cells. Patients who are treated with L-asparaginase should be observed carefully for several hours after dosing, and epinephrine should be available in case anaphylactic reactions occur. Anaphylaxis is less likely when L-asparaginase is given intramuscularly than when it is administered by the intravenous route.
The other major toxic effects of L-asparaginase are due to the ability of this drug to inhibit protein synthesis in normal tissues.101 Inhibition of protein synthesis in the liver will result in hypoalbuminemia, a decrease in clotting factors, a decrease in serum lipoproteins, and a marked increase in plasma triglycerides. Inhibition of insulin production may lead to hypoglycemia. The clotting abnormalities that are regularly observed as a consequence of L-asparaginase treatment include initial decreases in the anticoagulant factors antithrombin III, protein C, and protein S, leading to either arterial or venous thrombosis in occasional patients. With more prolonged therapy, bleeding sequelae may result from inhibition of the synthesis of procoagulant proteins such as fibrinogen and factors II, VII, IX, and X. Monitoring coagulation factors is therefore recommended. High doses of L-asparaginase may cause cerebral dysfunction manifested as confusion, stupor, and coma, and cortical sinus thrombosis has been documented by MRI scan in such patients.102 Acute nonhemorrhagic pancreatitis occurs as a complication of L-asparaginase treatment, especially in patients who have extreme elevations of plasma triglycerides (>2 g/dL).103
Inasmuch as L-asparaginase manifests little toxicity in marrow or gastrointestinal mucosa, this drug has been used in combination with other drugs that do have such toxicities. It rescues normal marrow cells from methotrexate toxicity, perhaps through its inhibition of protein synthesis, and can be used to prevent myelosuppression if administered following high-dose methotrexate.104 This combination has produced clinical responses in patients with acute leukemia refractory to conventional methotrexate doses.
These drugs are important in the treatment of hematopoietic malignancies either as single agents or as components of combination regimens. Their role as treatment for both acute and chronic hematologic malignancies results from their lack of cell cycle specificity. In combination with cell cycle–specific agents they may eradicate noncycling cells that escape cycle-active components of the treatment. While these agents share the common property of forming covalent bonds with electron-rich sites on DNA (oxygen and nitrogen substituents), they exhibit important differences in their intrinsic reactivity, route of cellular uptake, favored sites of alkylation on DNA bases, and the specific mechanism of DNA repair that determines cell survival. These differences are borne out in experimental settings, where cross-resistance to alkylating agents is not complete. Thus, protocols employing multiple alkylators, particularly in high-dose regimens, have a rational basis.105 Alkylating agents differ as well in their patterns of toxicity. The majority of these drugs cause myelosuppression and mucositis as their primary acute toxicities, as well as delayed pulmonary fibrosis and late secondary leukemias. They also cause vascular endothelial damage in occasional patients when used in high doses. However, cyclophosphamide and BCNU cause less mucositis in high-dose regimens, although cyclophosphamide rarely produces a hemorrhagic myocarditis. 4-Hydroperoxycyclophosphamide, an activated analog of cyclophosphamide, appears to spare marrow stem cells relative to tumor cells and is used for in vitro purging of marrow in autologous transplantation.106
All alkylating agents have in common the generation of highly reactive carbonium intermediates that attack electron-rich sites on DNA, such as the N-7, O-2, and O-6 positions of guanine and the N-1, N-3, and N-7 positions of adenine. For many of these agents, the alkylating group must undergo a preliminary activation reaction mediated either by chemical rearrangement of the molecule, as in the case of nitrogen mustard and the nitrosoureas, or by metabolic activation followed by chemical rearrangement, as for cyclophosphamide, ifosfamide, and procarbazine. In some alkylating agents the reactive intermediate contains two reactive centers, usually chloroethyl groups, and therefore may cross-link opposing strands of DNA. Methylating agents produce only single-strand alkylation but may be highly carcinogenic, as, for example, procarbazine and dacarbazine. In general, the most commonly used drugs of this class, including cyclophosphamide, ifosfamide, melphalan, and chlorambucil, produce the same spectrum of myelosuppressive, carcinogenic, and genotoxic actions.
Mechanisms of resistance to alkylating agents that are unique to these compounds have been elucidated in experimental systems.107 Some mechanisms are specific for certain alkylating agents (e.g., impaired uptake of nitrogen mustard as a consequence of an alteration in the membrane carrier for choline, or deletion of the amino acid carrier used by melphalan), while others appear to be less specific (e.g., drug inactivation associated with an increase in intracellular sulfhydryl compounds, and enhanced nucleotide excision-repair of DNA cross-links). The primary resistance mechanisms for various alkylating drugs, as documented in experimental tumors, include: increased degradation by aldehyde dehydrogenase (cyclophosphamide)108; increased conjugation of the reactive intermediates with glutathione or glutathione transferase (all chloroethylating agents and platinum analogs); increased repair of the O-6 guanine alkyl lesions by a specific alkyl transferase (nitrosoureas, procarbazine, dacarbazine)109; increased nucleotide excision repair (all platinum derivatives and chloroethylating agents, except nitrosoureas); decreased uptake (melphalan, nitrogen mustard); and decreased ability to recognize DNA damage (alkylating agents and platinum derivatives). The clinical basis of alkylating agent resistance is incompletely understood.
In general, the alkylating agents and their reactive intermediates have short residence times in the systemic circulation and within cells. They are eliminated predominantly by hydrolysis, chemical or biochemical conjugation to the sulfhydryl groups of glutathione or proteins, or by oxidative metabolism; therefore, dose reduction is not required in patients with diminished renal function. Cyclophosphamide and ifosfamide are closely related molecules that undergo hepatic activation. Their active metabolites generate a highly toxic metabolite, acrolein, that is excreted in the urine.110 In order to counteract toxicity to kidneys and bladder, mercaptoethane sulfonate (MESNA) is administered simultaneously in equivalent doses to patients receiving ifosfamide or high-dose cyclophosphamide. Nitrogen mustard is a highly reactive compound that may be administered topically, intravenously, or intrapleurally. It is a potent vesicant, and care must be taken in the mixing and administration of the drug. Extravasation may lead to severe tissue injury. The second-generation alkylating agents, which include cyclophosphamide, melphalan, busulfan, and chlorambucil, are more chemically stable and absorbed reasonably well when given orally.
Marrow toxicity, which is cumulative and a function of total dose, is the most important toxic effect of these compounds. Other toxicities, including lung, cardiac, and endothelial damage, have been described above. Since alkylating agents all react with DNA, mutations and secondary leukemias are major long-term effects of these agents. This hazard appears to be related to the total dose administered. The monofunctional methylating agents (e.g., procarbazine) are especially potent in this regard and may have a major role in the increased incidence of secondary malignancies noted in patients who have been treated with chemotherapy. The dose-limiting toxicity of one of these drugs, dacarbazine, is nausea and vomiting rather than marrow suppression.
Nitrosoureas produce a characteristic delayed myelosuppression that reaches a nadir 4 to 6 weeks after administration. Busulfan, like the nitrosoureas, depletes stem cells and can cause profound marrow hypoplasia or permanent aplasia when administered over prolonged periods of time and must be used with caution. All alkylating agents, but particularly busulfan and the nitrosoureas, may produce pulmonary fibrosis. The nitrosoureas also cause nephrotoxicity, particularly after total doses of 1200 mg/m2 BCNU or methylcyclohexylchloroethylnitrosourea.111
The development of marrow stem cell rescue techniques has made it clinically possible to administer doses of chemotherapy that would otherwise produce life-threatening aplasia. In order to be of benefit, however, high-dose therapy must employ agents that have a relatively steep dose–response relationship and must not have lethal extramedullary toxicity at high doses. Among the classes of cytotoxics, alkylators have a particularly favorable linear relationship between dose and cytotoxicity in experimental systems. Their hematopoietic toxicity is generally limiting within standard dose ranges, but other organ toxicities are infrequent until doses are increased manyfold, making them ideal candidates for high-dose regimens. When agents are administered with stem cell rescue, marrow toxicity ceases to be dose limiting and extramedullary toxic effects are seen. Depending on the agent and the toxicity profile, doses may only be escalated by as little as 2-fold, as seen with cisplatin because of renal toxicity, or to as high as 18-fold in the case of thiotepa (Table 16-3).112,113,114,115,116,117 and 118 However, when agents are combined into a high-dose regimen, overlapping extramedullary toxicities of the agents must be considered in order to avoid serious new additive and/or synergistic toxicities (Table 16-4). Overlapping extramedullary toxicities (particularly the risk of pulmonary or hepatic dysfunction or secondary leukemia) cannot be completely avoided, but rational drug selection can minimize the dose reductions of the individual agents, compared to their single-agent maximum tolerated dose, that are required to make a combination regimen safe. This is illustrated in Table 16-4, which shows the fraction of the single agent MTD that can be administered in combination with other drugs. As might be expected, this fraction is quite variable depending on the drug combinations, with the average fractional MTD used in combination ranging from 0.5 to 1. Depending on the regimen, significant gastrointestinal, pulmonary, hepatic, and/or renal toxicities are encountered and become dose limiting. For these reasons, high-dose regimens are safest in patients who are younger (<70 years) and who have had minimal prior chemotherapy and radiation therapy.



A variety of chemical agents have the ability to cause differentiation of malignant cells.119 The most prominent of these are members of the vitamin A family (carotenes and retinoids), vitamin D and its analogs, phenylacetic acid, cytotoxic agents used in low concentrations (such as cytosine arabinoside and 5-azacytidine), and a broad chemical class known as polar-planar differentiation agents, of which hexamethylene bisacetamide (HMBA) is the most extensively studied.120 In addition, biological agents such as the interferons and interleukins induce differentiation of both malignant and normal cells, but the role of differentiation in the anticancer action of these drugs in humans is uncertain, as they have multiple biological effects. Among the differentiating agents, the retinoids are the only drugs that have clearly identified therapeutic value in the treatment and prevention of cancer, although HMBA has produced interesting early results.
Two retinoids, 13-cis-retinoic acid (cRA) and all-trans-retinoic acid (tRA), are used clinically. cRA prevents the development of second malignancy in patients with head and neck cancer121 and when used with interferon induces a 50 percent response rate in squamous carcinomas of the skin122 and cervix,123 while tRA induces complete responses in a high percentage of patients with APL.124 This discussion will be confined to tRA, although other retinoids may find clinical utility in the treatment of hematologic disease in the future.
tRA acts through binding to a nuclear receptor formed by the heterodimerization of the RAR-a receptor and the retinoid X receptor. In APL, an abnormal fusion protein, composed of portions of the RAR-a receptor and a unique transcription factor (the PML gene product) results from the characteristic 15;17 chromosomal translocation found in this disease.125 The basis for the transforming properties of this mutant protein and the reasons for the sensitivity of APL cells to the differentiating activity of retinoids undoubtedly relate to the disordered retinoid receptor status but are not understood. It is not known whether the fusion protein has physiologic activity, although a functional RAR-a receptor seems essential to the expression of the differentiating effects of tRA in leukemic cells. In experimental settings, resistance to tRA differentiating activity results from mutation in the PML-RAR-a fusion gene, indicating that the fusion gene product plays a role in retinoid responsiveness, and sensitivity can be restored by transfection of a functional RAR-a gene.126
tRA is administered to APL patients in doses of 45 mg/m2 per day until complete remission is achieved and reaches peak serum levels of 300 ng/mL 1 to 2 h after administration.127 It disappears from serum with a half-life of less than 1 h during the initial course of treatment, but its rate of clearance greatly accelerates with continued treatment, a factor that may contribute to resistance to tRA therapy. Induction of CYP-mediated metabolism is suspected to underlie this accelerated clearance.128 The primary toxicities of tRA resemble those of other retinoids and vitamin A, specifically dry skin, cheilitis, mild and reversible hepatic dysfunction, bone tenderness and hyperostosis on x-ray, and occasional cases of pseudotumor cerebri; in addition, about 15 percent of patients with APL, particularly those with an initial white blood cell count greater than 5000 per mm3, develop a syndrome of hyperleukocytosis, fever, and respiratory failure (the “retinoic acid syndrome”).129 Hyperleukocytosis results from a rapid increase in the number of mature leukemic cells in the blood and from the increased expression of integrins on the leukemic cell surface in response to tRA. In patients with white blood cell counts above 20 × 103 cells per µL (20 × 109 cells/liter), pleural and pericardial effusions and peripheral edema develop rapidly, and respiratory distress, cardiac failure, and renal insufficiency may lead to death. Anecdotal reports indicate that high-dose glucocorticoids may reverse these findings, which is mediated by leukocyte adhesion and clogging of small vessels and/or by cytokine release.129 The early introduction of cytotoxic chemotherapy during remission induction, or the use of Decadron (10 mg twice daily for 3 or more days), may lower the incidence of the syndrome.130
Arsenic had been used in the treatment of chronic myelogenous leukemia and other malignancies in the 1930s with little effect. It has reappeared as an effective therapy for promyelocytic leukemia when used in the form of arsenic trioxide (As2O3), which induces differentiation and apoptosis in APL cells131 and produces remissions in most patients refractory to tRA and conventional chemotherapy. Remissions appeared in 2 to 3 months after beginning doses of 0.15 mg/kg/day for 25 days every 3 to 6 weeks, with evidence of leukemic cell differentiation and a progressive peripheral blood leukocytosis after 2 weeks of therapy.132,133 No consistent side effects have been observed, although occasional patients complain of fatigue, dysesthesias, and lightheadedness. A maximum plasma concentration of 5.5 to 7.3 µM was achieved in the initial studies from China, and small amounts of drug are eliminated in the urine, the rest residing in tissues.133

Goodman LS, Wintrobe MM, Dameshek W, et al: Nitrogen mustard therapy: Use of methylbis (B-chlorethyl) amino hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 132:126, 1946.

Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787, 1948.

Doney K, Fisher LD, Appelbaum FR, et al: Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse and relapse-free survival. Bone Marrow Transplant 7:453, 1991.

Hartwell L: Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71:543, 1992.

Boral A, Dessain S, Chabner B: Clinical evaluation of biologically targeted drugs: obstacles and opportunities. Cancer Chemother Pharmacol 42(suppl):S3, 1998.

Vokes EE, Schilsky RL, Weichselbaum RR, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: A clinical and pharmacologic analysis. J Clin Oncol 8:241, 1990.

Seitz JF, Giovanni M, Padaut-Cesana J, Fuentes C: Inoperable nonmetastatic squamous cell carcinoma of the esophagus managed by concomitant chemotherapy (5-fluorouracil and cisplatin) and radiation therapy. Cancer 66:214, 1990.

Leichman L, Nigro N, Vaitkevicius VK, et al: Cancer of the anal canal: Model for preoperative adjuvant combined modality therapy. Am J Med 78:211, 1985.

Omura GA, Bundy BN, Berek JS, et al: Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 7:457, 1989.

Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in Phase II studies in patients with cancer. J Clin Oncol 16:187, 1998.

Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727, 1979.

Endicott JA, Ling V: The biochemistry of p-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58:137, 1989.

Van der Kolk, de Vries E, Loning J, et al: Activity and expression of the multidrug resistance proteins MRP1 and MRP2 in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells. Clin Cancer Res 4:1727, 1998.

Dalton WS, Grogan TM: Does P-glycoprotein predict response to chemotherapy, and if so, is there a reliable way to detect it? J Natl Cancer Inst 83:80, 1991.

Göker E, Waltham M, Kheradpour A, et al: Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 86:677, 1995.

Fink D, Aebi S, Howell S: The role of DNA mismatch repair in drug resistance. Clin Cancer Res 4:1, 1998.

Kirsch D, Kastan M: Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 16:3158, 1998.

Hannun Y: Apoptosis and the dilemma of cancer chemotherapy. Blood 89(6):1845, 1997.

Moscow JA, Connolly T, Myers TG, et al: Reduced folate carrier gene (RFC1) expression and anti-folate resistance in transfected and non-selected cell lines. Int J Cancer 72:184, 1997.

Ross JF, Chaudhuri PK, Ratnam M: Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73:2432, 1994.

Galpin A, Schuetz J, Mason E, et al: Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytoxicity. Mol Pharmacol 52:155, 1997.

Synold TW, Relling MV, Boyett JM, et al: Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest, 94:1996, 1994.

Longo GS, Gorlick R, Tong WP, et al: Gamma-glutamyl hydrolase and folylployglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemia. Oncol Res 9:259, 1997.

Dicker AP, Volkenandt M, Schweitzer BI, et al: Identification and characterization of a mutation in the dihydrofolate reductase gene from the methotrexate-resistant Chinese hamster ovary cell line Pro-3 MTXRIII. J Biol Chem 265:8317, 1990.

Evans W, Crom W, Abromowitch M, et al: Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia: identification of a relation between concentration and effect. N Engl J Med 314:471, 1986.

Stoller RG, Hande KR, Jacobs SA, et al: Use of plasma pharmaco-kinetics to predict and prevent methotrexate toxicity. N Engl J Med 297:630, 1977.

Widemann BC, Balis FM, Murphy RF, et al: Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate- induced renal dysfunction. J Clin Oncol 15:2125, 1997.

Shapiro WR, Allen JC, Horten BC: Chronic methotrexate toxicity to the central nervous system. Clin Bull Memorial-Sloan Kettering 10:49, 1980.

Bloomfield CD, Lawrence D, Byrd JC, et al: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58:4173, 1998.

Kufe DW, Munroe D, Herrick D, et al: Effects of 1-b-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function. Mol Pharmacol 26:128, 1984.

Owens JK, Shewach DS, Ullman B, Mitchell RS: Resistance to 1-b-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer Res 52:2389, 1992.

Flasshove M, Strumberg D, Ayscue L, et al: Structural analysis of the deoxycytidine kinase gene in patients with the acute myeloid leukemia and resistance to cytosine arabinoside. Leukemia 8:780, 1993.

Capizzi RL, Powell BL: Sequential high-dose ara-C and asparaginase versus high-dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. Semin Oncol 14(suppl 1):40, 1987.

Glantz MJ, Jaeckle KA, Chamberlain MC, et al: A Randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5:3394, 1999.

Kern W, Kurrle E, Schmeiser T: Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy. A review of 55 cases. Infection 18:138, 1990.

Herzig RH, Hines JD, Herzig GP, et al: Cerebellar toxicity with high- dose cytosine arabinoside. J Clin Oncol 5:927, 1987.

Ley TJ, DeSimone J, Anagnon NP, et al: 5-Azacytidine selectively increases gamma chain synthesis in a patient with b-thalassemia. N Engl J Med 307:1469, 1982.

Drake JC, Stoller RG, Chabner BA: Characteristics of the enzyme uridine-cytidine kinase isolated from a cultured human cell line. Biochem Pharmacol 26:64, 1977.

Christie NT, Drake S, Meyn RE, et al: 6-Thiopurine-induced DNA damage as a determinant of cytotoxicity in cultured Chinese hamster ovary cells. Cancer Res 44:3665, 1984.

Lilleyman J, Lennard L: Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 343:1188, 1994.

Van Diggelen OP, Donahue TF, Shin SI: Basis for differential cellular sensitivity to 8-azaguanine and 6-thioguanine. J Cell Physiol 98:59, 1979.

Scholar EM, Calabresi P: Increased activity of alkaline phosphatases in leukemic cells from patients resistant to thiopurines. Biochem Pharmacol 28:445, 1979.

Lennard L, Lillyman JS: Are children with lymphoblastic leukaemia given enough 6-mercaptopurine? Lancet 2:785, 1987.

Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM: Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225, 1990.

Zimm S, Collins JM, Riccardi R, et al: Variable bioavailability of oral 6-mercaptopurine: Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 308:1005, 1983.

Lennard L, Davies HA, Lilleyman JS: Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia. Br J Canc 68:186, 1993.

Keating MJ, O’Brien S, Lerner S, et al: Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 92(4):1165, 1998.

Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91(3):756, 1998.

Brockman RW, Cheng Y-C, Schabel FM Jr, et al: Metabolism and chemotherapeutic activity of 9-b-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res 40:3610, 1980.

Plunkett W, Gandhi V: Pharmacology of purine nucleoside analogues. Hematol Cell Ther 38(suppl 2):67, 1996.

Fan S, el-Deiry WS, Bae I, et al: p53 Gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 54:5824, 1994.

Cheson B, Frame J, Vena D, et al: Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 16:2313, 1998.

Cheson BD: Immunologic and immunosuppressive complications of purine analogue therapy. J Clin Oncol 13:2431, 1995.

Estey EH, Kurzrock R, Kantarjin HM, et al: Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA). Blood 79:882, 1992.

Kay AC, Saven A, Carrera CJ, et al: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 10:371, 1992.

Albertoni F, Lindemalm S, Reichelova V, et al: Pharmacokinetics of cladribine in plasma and its 5-monophosphate and 5-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia 1. Clin Cancer Res 4:653, 1998.

Beutler E: Cladribine (2-chlorodeoxyadenosine). Lancet 340:952, 1992.

Saven A, Piro L: 2-chlorodeoxyadenosine: A newer purine analogue active in the treatement of indolent lymphoid malignancies. Ann Intern Med 120:784, 1994.

Mitchell BS, Edwards NL, Koller CA: Deoxyribonucleoside triphosphate accumulation by leukemic cells. Blood 62:419, 1983.

Steis R, Urba WJ, Kopp WC, et al: Kinetics of recovery of CD4+ cells in peripheral blood of deoxycoformycin-treated patients. J Natl Cancer Inst 83:1678, 1992.

Madoc-Jones H, Mauro F: Interphase action of vinblastine and vincristine: Differences in their lethal action through the mitotic cycle of cultured mammalian cells. J Cell Physiol 72:185, 1968.

Cabral FR, Brady RC, Schiber MJ: A mechanism of cellular resistance to drugs that interfere with microtubule assembly. Ann NY Acad Sci 46:748, 1986.

Wilson WH, Chabner BA, Bryant G, et al: A phase II study of paclitaxel (Taxol) in relapsed non-Hodgkin’s lymphomas. J Clin Oncol 13:381, 1995.

Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 332:1004, 1995.

Consolini R, Ching-Hon P, Behn FG: In vitro cytoxicity of docetaxel in childhood acute leukemias. J Clin Oncol 16(3):907, 1998.

Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell cycle effects of Taxol on human hamster ovarian cell lines. Cancer Chemother Pharmacol 32:235, 1993.

Gianni L, Vigano L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15:1906, 1997.

Semb K, Aamdal S, Oian P: Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 16(10):3426, 1998.

Ohno R, Okada K, Masaoka T, et al: An early phase II study of CPT- 11: A new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 8:1907, 1990.

Beran M, Kantarjian H, Obrien S, et al: Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 88:2473, 1996.

Iyer L, King C, Whitington P, et al: Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847, 1998.

Grochow LB, Rowinski EK, Johnson R, et al: Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos 20:706, 1992.

Capranico G, Butelli E, Zunnino F: Change of the sequence specificity of daunorubicin-stimulated topoisomerase II DNA cleavage by epimerization of the amino group of the sugar moiety. Cancer Res. 55:312, 1995.

Reid JM, Pendergrass TW, Krailo MD, et al: Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: A Children’s Cancer Study Group report. Cancer Res 50:6525, 1990.

Moreb JS, Oblon DJ: Outcome of clinical congestive heart failure induced by anthracycline chemotherapy. Cancer 70:2637, 1992.

Speyer JL, Green MD, Kramer E, et al: Protective effect of the bispiperazinedione, ICRF-187, against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 319:745, 1988.

Billingham ME, Bristow MR, Glatstein E, et al: Adriamycin cardiotoxicity: Endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol 1:17, 1977.

Lipschultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin in therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808, 1991.

Nysom K, Holm K, Lipsita S: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16(2):545, 1998.

Odom LF, Gordon EM: Acute monoblastic leukemia in infancy and early childhood: Successful treatment with an epipodophyllotoxin. Blood 64:875, 1984.

Capranico G, Zunino F: Antitumor inhibitors of DNA topoisomerases. Curr Pharm Des 1:1, 1995.

Zwelling LA, Hinds M, Chan D, et al: Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug resistant form of topoisomerase II. J Biol Chem 264:16411, 1989.

Buggs BY, Danks MK, Beck WT, Suttle DP: Expression of a mutant topoisomerase II in CCRF-CEM human leukemia cells selected for resistance to teniposide. Proc Natl Acad Sci USA 88:7654, 1991.

Stewart CF, Arbuck SG, Fleming RA, et al: Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8:1874, 1990.

Winick N, McKenna R, Shuster JJ, et al: Secondary acute myeloid leukemia in children with B-lineage acute lymphoblastic leukemia treated with an epipodophyllotoxin. J Clin Oncol 11:209,1993.

Ratain MJ, Kaminer LS, Bitran JD, et al: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 70:1412, 1987.

Umezawa H, Maeda K, Takeuchi T, et al: New antibiotics, bleomycin A and B. J Antibiot Ser A 19:200, 1966.

Petering DH, Byrnes RW, Antholine WE: The role of redox-active metals in the mechanism of action of bleomycin. Chem Biol Interact 73:133, 1990.

Burger RM, Drlica K, Birdsall B: The DNA cleavage pathway of iron BLM strand scission precedes deoxyribose 3-phosphate bond cleavage. J Biol Chem, 269:25978, 1994.

Burger R: Cleavage of nucleic acids by bleomycin. Chem Rev 98:1153, 1998.

Sebti SM, Jani JP, Mistry JS, et al: Metabolic inactivation: A mechanism of human tumor resistance to bleomycin. Cancer Res 51:227, 1991.

Alberts DS, Chen HSG, Liu R, et al: Bleomycin pharmacokinetics in man: I. Intravenous administration. Cancer Chemother Pharmacol 1:177, 1978.

Karmiol S, Remick DG, Kunkel SL, Phan SL: Regulation of rat pulmonary endothelial cell interleukin-6 production by bleomycin: Effects of cellular fatty acid composition. Am J Respir Cell Mol Biol, 9:628, 1993.

Blum RH, Carter SK, Agre K: A clinical review of bleomycin—a new antineoplastic agent. Cancer 31:903, 1973.

Comis RL: Detecting bleomycin pulmonary toxicity: A continued conundrum. J Clin Oncol 8:765, 1990.

Hutson RG, Kitoh T, Moraga Amador DA: Amino acid control of asparagine synthetase: relation to asparaginase resistance in human leukemia cells. Am J Physiol 272:1691, 1997.

Kaspers GJ, Veerman AJ, Pieters R, et al: In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. Blood 90:2723, 1997.

Asselin BL, Whitin JC, Coppola DJ, et al: Comparative pharmacokinetic studies of three asparaginase preparations, J Clin Oncol. 11:1780, 1993.

Holle LM: Pegaspargase: An alternative? Ann Pharmacother 31:616, 1997.

Killander D, Dohlwitz S, Engstedt L, et al: Hypersensitive reactions and antibody formation during L-asparaginase treatment of children and adults with acute leukemia. Cancer 37:220, 1976.

Semeraro N, Montemurro P, Giordano P, et al: Unbalanced coagulation fibrinolysis potential during L-asparaginase therapy in children with acute lymphoblastic leukaemia. Thromb Haemost 64:38, 1990.

Bushara KO, Rust RS: Reversible MRI lesions due to pegaspargase treatment of non-Hodgkin’s lymphoma. Pediatr Neurol 17:185, 1997.

Parsons SK, Skapek SX, Neufeld EJ, et al: Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood 89:1886, 1997.

Capizzi R: Improvement in the therapeutic index of L-asparaginase by methotrexate. Cancer Chemother Rep 6(3):37, 1975.

Peters WP, Shpall EJ, Jones RB, et al: High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 6:1368, 1988.

Yeager AM, Kaizer H, Santos GW, et al: Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315:141, 1986.

Tew KD, Colvin M, Chabner BA: Alkylating agents, in Cancer Chemotherapy and Biotherapy: Principles and Practice, 2nd ed, edited by BA Chabner, DL Longo, pp 297–332. Lippincott, Philadelphia, PA, 1996.

Hilton J: Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. Cancer Res 44:5156, 1984.

Erickson L: The role of O-6 methylguanine DNA methyltransferase (MGMT) in drug resistance and strategies for its inhibition. Sem Cancer Biol 2:257, 1991.

Droller MJ, Saral R, Santos G: Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology 20:256, 1982.

Schacht RG, Baldwin DS: Chronic interstitial nephritis and renal failure due to nitrosourea (NU) therapy. Kidney Int 14:661, 1978.

Gianni AM, Bregni M, Siena S, et al: Recombinant human granulocyte- macrophage colony stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin’s lymphoma. J Clin Oncol 8:768, 1990.

Elias AD, Eder JP, Shea T, et al: High-dose ifosfamide with mesna uroprotection: A phase I study. J Clin Oncol 8:170, 1990.

Lazarus HM, Reed MD, Spitzer TR, et al: High-dose IV thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep 71:689, 1987.

Peters WP, Henner WD, Grochow LB, et al: Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res 47:6402, 1987.

Phillips GL, Wolff SN, Fay JW, et al: Intensive 1,3-bis(2-chloroethyl)- 1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma. J Clin Oncol 4:639, 1986.

Ozols RF, Corden BJ, Jacob J, et al: High dose cisplatin in hypertonic saline. Ann Intern Med 100:19, 1984.

Shea TC, Flaherty M, Elias A, et al: A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 7:651, 1989.

Parkinson DR, Smith MA: Retinoid therapy for acute promyelocytic leukemia: A coming of age for the differentiation therapy of malignancy (Editorial). Ann Intern Med 117:338, 1992.

Andreeff M, Stone R, Michaeli J, et al: Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: A phase II clinical trial with a differentiation-inducing agent. Blood 80:2504, 1992.

Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323:795, 1990.

Lippman SM, Parkinson DR, Weber RS, et al: Isotretinoin plus alpha interferon: Effective therapy of advanced squamous cell carcinoma (scc) of the skin. Proc Am Soc Clin Oncol 10:A650, 1991.

Lippman SM, Kavanagh JJ, Paredes-Espinoza J, et al: 13-cis-Retinoic acid plus interferon alpha-2a: Highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 84:241, 1992.

Warrell RP Jr, Frankel SR, Miller WH Jr, et al: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 324:1385, 1991.

Kazizuka A, Miller WH Jr, Umesono K, et al: Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARa with a novel putative transcription factor, PML. Cell 66:663, 1991.

Robertson KA, Emami B, Collins SJ: Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand binding domain that confers dominant negative activity. Blood 80:1885, 1992.

Muindi JRF, Frankel SR, Huselton C, et al: Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res 52:2138, 1992.

Muindi J, Frankel SR, Miller WH Jr, et al: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: Implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 79:299, 1992.

Frankel SR, Eardley A, Lauwers G, et al: The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 117:292, 1992.

De Botton S, Dombret H, Sanz M, et al: Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. Blood 92(8):2712.

Soignet SL, Maslak P, Wang Z-G, et al: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339(19):1341, 1998.

Chen G-Q, Shi X-G, Tang W, et al: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89:3345, 1997.

Shen Z-X, Chen G-Q, Ni J-H, et al: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89(9):3354, 1997.

Eder JP, Elias A, Shea TC, et al: A phase I–II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients. J Clin Oncol 8:1239, 1990.

Kessinger A, Armitage JO, Smith DM, et al: High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma. Blood 74:1260, 1989.

Jones RJ, Piantadosi S, Mann RB, et al: High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol 8:527, 1990.

Wilson WH, Jain V, Bryant G, et al: Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors. J Clin Oncol 10:1712, 1992.

Dunphy FR, Spitzer G, Buzdar AU, et al: Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support. J Clin Oncol 8:1207, 1990.

Sterkers Y, Preudhomme C, Lai J-L, et al: Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 91:616, 1998.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



  1. Check for U.S. clinical trials from NCI’s list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia . The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

  2. […] #split {}#single {}#splitalign {margin-left: auto; margin-right: auto;}#singlealign {margin-left: auto; margin-right: auto;}#splittitlebox {text-align: center;}#singletitlebox {text-align: center;}.linkboxtext {line-height: 1.4em;}.linkboxcontainer {padding: 7px 7px 7px 7px;background-color:#eeeeee;border-color:#000000;border-width:0px; border-style:solid;}.linkboxdisplay {padding: 7px 7px 7px 7px;}.linkboxdisplay td {text-align: center;}.linkboxdisplay a:link {text-decoration: none;}.linkboxdisplay a:hover {text-decoration: underline;} function opensplitdropdown() { document.getElementById('splittablelinks').style.display = ''; document.getElementById('splitmouse').style.display = 'none'; var titleincell = document.getElementById('titleincell').value; if (titleincell == 'yes') {document.getElementById('splittitletext').style.display = 'none';} } function closesplitdropdown() { document.getElementById('splittablelinks').style.display = 'none'; document.getElementById('splitmouse').style.display = ''; var titleincell = document.getElementById('titleincell').value; if (titleincell == 'yes') {document.getElementById('splittitletext').style.display = '';} } What is the difference in the stages of colon cancer?Well Blog: Colon Cancer Advances Show Black-White DivideCancer Holistic TreatmentsCHAPTER 16 PHARMACOLOGY AND TOXICITY OF ANTINEOPLASTIC DRUGS […]

  3. […] #split {}#single {}#splitalign {margin-left: auto; margin-right: auto;}#singlealign {margin-left: auto; margin-right: auto;}#splittitlebox {text-align: center;}#singletitlebox {text-align: center;}.linkboxtext {line-height: 1.4em;}.linkboxcontainer {padding: 7px 7px 7px 7px;background-color:#eeeeee;border-color:#000000;border-width:0px; border-style:solid;}.linkboxdisplay {padding: 7px 7px 7px 7px;}.linkboxdisplay td {text-align: center;}.linkboxdisplay a:link {text-decoration: none;}.linkboxdisplay a:hover {text-decoration: underline;} function opensingledropdown() { document.getElementById('singletablelinks').style.display = ''; document.getElementById('singlemouse').style.display = 'none'; } function closesingledropdown() { document.getElementById('singletablelinks').style.display = 'none'; document.getElementById('singlemouse').style.display = ''; } Your Acne Environment – Acne Home Remedy Tips…Fight Cancer Cells With ChemotherapyAcne Prevention Tips And Home RemediesQ&A: what is the best home remedy for sore throat?Myth: Too Much Sex Causes Prostate CancerAnti-Breast Cancer Activity of a PapayaIf you have cancer that spreads to lymph nodes, what is it called?CHAPTER 16 PHARMACOLOGY AND TOXICITY OF ANTINEOPLASTIC DRUGS […]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s

%d bloggers like this: