Cancer Chemotherapy & Biotherapy: Principles & Practices, 4th Edition

Purine Antimetabolites

Kenneth R. Hande


(6-Mercaptopurine, 6-Thioguanine, and Azathioprine)

More than 50 years after its initial use, 6-mercaptopurine (6-MP) is still employed as primary therapy for children with acute lymphoblastic leukemia (ALL)1. 6-Thioguanine (6-TG) is given for remission induction and maintenance therapy of acute myelogenous leukemia. Azathioprine, a prodrug of 6-MP, is widely used as an immunosuppressant. These three drugs are closely related in structure (Fig. 9.1), metabolism, mechanism of action, and toxicity. Because of their similarities, they will be discussed together in this section. The key pharmacologic features of these drugs are summarized in Tables 9.1, 9.2, 9.3

Mechanism of Action

6-MP is a structural analog of hypoxanthine with a substitution of a thiol for the naturally occurring 6-hydroxyl group (Fig. 9.1). 6-MP undergoes extensive hepatic and cellular metabolism after dosing.2 Three major competing transformation routes are present, one anabolic and two catabolic. 6-MP is activated intracellularly by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form 6-thioinosine monophosphate (TIMP). TIMP inhibits de novo purine synthesis (Fig. 9.2). Sequential metabolism of TIMP to thioguanine monophosphate and then to 6-thioguanosine triphosphate (6-TGTP) occurs. 6-TGTP is incorporated into DNA and RNA. The quantity of 6-MP metabolite present in DNA correlates with cytotoxicity.3 Incorporation of 6-TGTP into DNA triggers programmed cell death by a process involving the mismatch repair pathway.4, 5 Cytotoxicity depends on (a) incorporation of 6-TG into DNA, (b) miscoding during DNA replication, and (c) recognition of the abnormal base pairs by proteins of the postreplicative mismatch repair system. Methylation of 6-MP contributes to its antiproliferation properties, probably through inhibition of de novo purine synthesis by methymercaptopurine nucleotides.6

6-TG is activated in a manner similar to that outlined for 6-MP.7 Thioguanine is converted to 6-thioguanylic acid (TGMP) by HGPRT. TGMP is subsequently incorporated into RNA and DNA in its deoxytriphosphate form. Incorporation of fraudulent nucleotides into DNA is believed to be the primary mechanism of cytotoxicity,8 triggering apoptosis by a process involving the mismatch repair pathway, similar to 6-MP.5 Conversion of 6-TG into cytotoxic thioguanine nucleotides involves fewer metabolic steps than needed for 6-MP. Significantly higher cellular concentrations of thioguanine nucleotides are seen after 6-TG administration than with 6-MP.9

Azathioprine (Fig. 9.1) is rapidly cleaved by nonenzymatic mechanisms to 6-MP and methyl-4-nitro-5-imidazole derivatives (Fig. 9.2). Although incorporation of false nucleotides into DNA and inhibition of purine synthesis by 6-MP ribonucleotides are the probable mechanism for cytotoxicity, the mechanism by which azathioprine and mercaptopurine modify immune response is likely different. Azathioprine inhibits T-lymphocyte activity to a greater extent than B-lymphocytes. Formation of 6-thioguanine triphosphate (6-TGTP) binds to and inhibits Rac 1, a small GTP-binding protein. Rac proteins play a major role in T cell development, differentiation, and proliferation The activation of Rac1 targeted genes, such as mitogen-activated protein kinase (MEK), NFk BI, and bcl-XL, is suppressed by azathioprine leading to the mitochondrial pathway of apoptosis.10

Clinical Pharmacology


6-MP is commercially available in 50-mg tablets, which also contain the inactive ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. An intravenous preparation of 6-MP has been formulated for research purposes. 6-MP is relatively insoluble and unstable in alkaline solutions.

Figure 9.1 Structure of the naturally occurring purine, guanine, and related antineoplastic agents 6-mercaptopurine, 6-thioguanine and azathioprine.

Plasma 6-MP, 6-TG, and metabolite concentrations as low as 0.1 µM can be measured using high-performance liquid chromatography techniques.11 Using these assays, accurate kinetics of oral and intravenous preparations have been determined. Following oral administration of commonly used 6-MP doses (75 mg/m2), peak plasma concentrations of 0.3 to 1.8 µM are seen within a mean of 2.2 hours.12 The volume of distribution exceeds that of total body water (0.9 L/kg). There is little penetration into the cerebrospinal fluid (CSF). With high-dose oral 6-MP (500 mg/m2), plasma 6-MP concentrations of 5 to 12 µM are achieved.13In human leukemic cell culture models, concentrations of 1 to 10 µM are cytotoxic. Following intravenous dosing, the half-life of 6-MP is 50 to 100 minutes and plasma concentrations of 6-MP reach 25 µM and CSF concentrations 3.8 µM.14 Only weak protein binding is noted with 6-MP (20% bound).




Mechanism of Action

1. Primary: Incorporation of metabolites into DNA causes miscoding during DNA replication. Correlates with cytotoxicity

2. Secondary: Inhibits de novo purine synthesis; incorporated into RNA.


Activation: conversion to thiopurine nucleotides
Catabolism: to 6-thiouric acid by xanthine oxidase
Catabolism: to 6-methylthiopurine by thiopurine methyltransferase(TPMT)


T½: 50 minutes
Poor (<25%) and variable oral bioavailability


Metabolism, at conventional doses, by xanthine oxidase and TPMT

Drug Interactions

Allopurinol decreases 6-MG elimination and concomitant use requires dose reduction (75%)


1. Myelosuppression

2. Mild gastrointestinal (nausea, vomiting)

3. Rare hepatotoxicity


1. Dose reductions with allopurinol

2. Persons with genetic deficiency of TPMT will have significantly increased toxicity (genetic screening available to test for TPMT deficiency)

Oral absorption of 6-MP is incomplete and highly variable.15 At a dose of 75 mg/m2 6-MP, mean 6-MP bioavailability is 16% (range, 5 to 37%).16 Clearance occurs primarily through two routes of metabolism. 6-MP is oxidized to the inactive metabolite, 6-thiouric acid, by xanthine oxidase (Fig. 9.2). 6-MP also undergoes S-methylation by the enzyme, thiopurine methyltransferase (TPMT), to yield 6-methyl mercaptopurine. The intestinal mucosa and liver contain high concentrations of the enzyme xanthine oxidase. The low bioavailability of 6-MP is the result of a large first-pass effect as drug is absorbed through the intestinal wall into the portal circulation and metabolized by xanthine oxidase. The use of concomitant allopurinol (an inhibitor of xanthine oxidase) increases 6-MP bioavailability by 500%.17 Interestingly, allopurinol does not alter the plasma kinetics of intravenously administered 6-MP, although more 6-MP and less thiouric acid is excreted in the urine following allopurinol therapy.18 Methotrexate, often used with 6-MP in maintenance treatment of acute lymphoblastic leukemia, is a weak inhibitor of xanthine oxidase. Concomitant use of methotrexate results in a small increase in the bioavailability of 6-MP. However, the modest increase in bioavailability is thought not to be clinically significant.15 The plasma concentration versus time profile of 6-MP differs in the same patient when studied on repeated occasions.19




Mechanism of Action

Incorporation of fraudulent nucleotides into DNA


Activation: conversion to thiopurine nucleotides
Catabolism: to 6-thioxanthine by guanase
Catabolism: to 2-amino-6-methyl thiopurine by thiopurine methyltransferase (TPMT)


T½: 90 minutes
Poor (15–40%) and variable bioavailability


Hepatic metabolism

Drug Interactions

None well defined


1. Myelosuppression

2. Mild gastrointestinal (nausea, vomiting)

3. Rare hepatotoxicity


Increased toxicity in individuals with genetic deficiency of TPMT

High-dose, oral 6-MP (500 mg/m2) has been used in an attempt to saturate the first-pass metabolism of 6-MP, thereby increasing bioavailability.13 Even at a dose of 500 mg/m2, 6-MP, xanthine oxidase is not saturated and no improvement in bioavailability is seen. Food intake and oral antibiotic reduce the oral absorption of 6-MP.20, 21

As previously mentioned, two catabolic pathways for 6-MP metabolism exist that significantly affect drug activity: one via xanthine oxidase (just discussed) and a second via thiopurine methyltransferase (TPMT). Patient-to-patient variation in TPMT activity results in significant changes in 6-MP metabolism and drug toxicity. As seen in Figure 9.2, TPMT catalyzes the S-methylation of 6-MP to a relatively inactive metabolite, 6-methyl mercaptopurine (6CH3MP). Interindividual TPMT activity is controlled by a common genetic polymorphism.22 (See chapter-Diasio) The frequency distribution of TPMT activity in large population studies is trimodal. One in 200 to 300 subjects has absent enzyme activity; 10% of the population has intermediate activity, and the rest have high enzyme activity.23 A number of polymorphic variants coding for varying levels of enzyme activity have been identified. A single genetic locus with two alleles is responsible for the trimodal distribution. Lymphoblasts from individuals heterozygous for the normal TMTP gene have lower TMPT activity than lymphoblasts from homozygous patients.24 Patients with low TPMT activity are more susceptible to 6-MP and 6-TG–induced myelosuppression. Marked myelosuppression in patients receiving 6-MP, 6-TG, or azathioprine therapy may be a result of genetic deficiency in TPMT activity in that patient.25 Patients with absence of TMPT activity should have the dose of 6-MP reduced, but not the dose of other chemotherapeutic agents given for their leukemia. There is a suggestion that Blacks may have less TPMT activity than Whites,26 which could increase toxicity in that population. A reciprocal relationship between TPMT activity and the formation of 6-thiopurine nucleotides has been demonstrated. Several studies27, 28, 29 but not all,16have suggested that variability in oral absorption of 6-MP may affect the risk of relapse in children with ALL. Lennard et al.30 have suggested that children with high TPMT activity are at greater risk of disease relapse as a result of decreased drug activation.




Mechanism of Action

Similar to 6-MP.


Rapidly converted to 6-MP by nonenzymatic mechanisms.


See 6-MP


Rapid metabolism to 6-MP and with subsequent elimination similar to 6-MP

Drug interactions

Allopurinol decreases elimination. Concomitant use with allopurinol requires azathioprine dose reductions (≥75%).


1. Myelosuppression

2. Gastrointestinal (nausea, vomiting)

3. Rare hepatotoxicity


1. Dose reduction with allopurinol required

2. Increased toxicity in individuals with genetic deficiency of thiopurine methyl-transferase

Figure 9.2 Mechanism of activation and catabolism of azathioprine and 6-MG. Active metabolites are indicated by surrounding boxes. Inactive (or less active) metabolites are indicated by italic print. CH3MP, 6-methyl mercaptopurine; TPMT, thiopurine methyltransferase; XO, xanthine oxidase.

The TPMT gene has been cloned. Eight TPMT polymorphisms associated with reduced enzyme activity have been identified.31 Variant TPMT alleles are present in 5 to 10% of persons in most populations.32 In describing gene mutations, the convention has been adopted that the nonmutated gene is designated a TPMT 1 and mutated genes are assigned as TPMT 2-8 on the basis of the order in which they were first described. In White populations, the most common mutation genotype associated with low enzyme activity is TPMT 3, which accounts for more than 80% of heterozygotes.33 Genetic testing using PCR-based methods can now identify TPMT-deficient and heterozygous patients.34 This test, as opposed to direct measurement of TPMT activity in red blood cells, is not affected by prior blood transfusions to the patient. Although dosage reductions have been suggested for patients with hepatic and renal function impairment, there is no good data justifying such dose adjustments. Dose adjustment for patients homozygous for mutant TPMT are required.


6-TG is available as 40-mg tablets for oral use. An intravenous preparation is investigational. As with 6-MP, the absorption of 6-TG in humans is variable and incomplete (mean bioavailability is 30%; range: 14 to 46%).35 Peak plasma levels of 0.03-5 µM occur 2 to 4 hours after ingestion; the median drug half-life is 90 minutes but with wide variability reported.36 Intravenously administered 6-TG has been evaluated. Clearance of drug (600 to 1,000 mL/min per square meter) appears to be dose-dependent, suggesting saturation of clearance at doses over 10 mg/m2 per hour.37 Plasma concentrations of 4 to 10 µM can be achieved.

The catabolism of 6-TG differs from that of 6-MP. Thioguanine is not a substrate for xanthine oxidase. Thioguanine is converted to 6-thioinosine (an inactive metabolite) by the action of the enzyme, guanase. Because thioguanine inactivation does not depend on the action of xanthine oxidase, an inhibitor of xanthine oxidase, such as allopurinol, will not block the detoxification of thioguanine. In humans, methylation of thioguanine, via thiopurine methyltransferase (TPMT), is more extensive than is that of 6-MP. The product of methylation, 2-amino-6-methylthiopurine, is substantially less active and less toxic than thioguanine.


Azathioprine is rapidly degraded by nonenzymatic mechanisms to 6-MP. The metabolic pathways thereafter are identical to 6-MP.38 In transplant patients taking 2 mg/kg per day azathioprine, peak 6-MP plasma concentrations (Tmax<2 hours) are low (75 ng/mL) and plasma drug half-life is short (1.9 hours).39Plasma 6-MP concentrations exceed those of azathioprine within an hour of drug administration. Loss of renal function does not alter the plasma kinetics of either azathioprine or 6-MP.




The dose-limiting toxicity of 6-MP is myelosuppression, occurring 1 to 4 weeks following the onset of therapy and reversible when the drug is discontinued. Platelets, granulocytes, and erythrocytes are all affected. Weekly monitoring of blood counts during the first 2 months of therapy is recommended. Myelosuppression following 6-MP therapy is related to TPMT phenotype. Most patients (65%) with excessive toxicity following 6-MP or azathioprine administration have TMPT deficiency or heterozygosity.40, 41

6-MP is an immunosuppressant. Immunity to infectious agents or vaccines is subnormal in patients receiving 6-MP. Gastrointestinal mucositis and stomatitis are modest. Approximately one-quarter of treated patients experienced nausea, vomiting, and anorexia. Gastrointestinal side effects appear to be more common in adults than in children. Pancreatitis is seen in 3% of patients with long-term therapy.41 Hepatotoxicity is noted infrequently and is usually mild and reversible.42 The development of hepatotoxicity, in contrast to myelosuppression, is not associated with TPMT polymorphisms,43 but is correlated with the dose of 6-MP given and with the formation of methylated metabolites of 6-MP (but not with 6-TG nucleotide formation).44

At very high doses (>1,000 mg/m2), the limited solubility of 6-MP can cause precipitation of drug in the renal tubules with hematuria and crystalluria.45Mercaptopurine has potential teratogenic properties.46 However, in a recent cohort analysis, differences in conception failures, congenital malformations, or incidence of neoplasia was not noted in patients taking 6-MP before or at the time of conception.47


As with 6-MP, the primary toxicity of 6-TG is myelosuppression.48 Blood counts should be frequently monitored because there may be a delayed effect during oral drug administration. Higher doses result in mucositis. Thioguanine produces gastrointestinal toxicities similar to 6-MP but less frequently. Jaundice and hepatic veno-occlusive disease have been reported.49


Adverse effects from azathioprine are similar to those seen with 6-MP. These effects include leukopenia, diarrhea, nausea, abnormal liver function tests and skin rashes. Frequent monitoring of the complete blood count is warranted throughout therapy (weekly during the first 8 weeks of therapy). A hypersensitivity reaction, generally characterized by fever, chills, severe nausea, diarrhea, hypertension, and hepatic dysfunction, has been reported.50 The mechanism for the hypersensitivity reaction is unclear. Chronic immunosuppressive therapy, including use of azathioprine, results in an increased frequency of secondary infections and an increased risk of malignant tumors.51 Acute myeloid leukemia associated with karyotypic changes of 7q-/-7 has been reported.52 Risk of cancer development increases with longer duration of azathioprine use (<5 years, the relative risk [RR] = 1.3; 5 to 10 years, RR = 2.0; >10 years, RR = 4.4).

Toxicity from azathioprine, primarily myelosuppression and gastrointestinal intolerance, requires dose adjustment or discontinuation of treatment in up to 40% of patients. Several studies53, 54 indicate that patients heterozygous for mutant TPMT are at high risk for toxicity and dose modification. In a study by Black et al.,53 all patients heterozygous for the TMPT 3A allele required discontinuation of therapy within 1 month. Molecular testing for TMPT may be a cost-effective way of identifying the 10% of the population at high risk for toxicity.32

Use and Drug Interactions

6-MP is a standard component of maintenance therapy for ALL. It has little role in therapy of solid tumors or remission induction in myeloid leukemias. 6-MP is also used to treat inflammatory bowel disease.

Azathioprine is used as an immunosuppressant in preventing rejection of organ transplants and in the therapy of illnesses believed autoimmune in character (such as lupus, rheumatoid arthritis, and ulcerative colitis).

As previously mentioned, allopurinol inhibits the catabolism of 6-MP and increases its bioavailability.17 Oral doses of 6-MP and azathioprine should be reduced by at least 75% in patients also receiving allopurinol. Combined use of standard dose azathioprine (or 6-MP) with allopurinol will result in life-threatening toxicity.55 Methotrexate causes a modest increase in 6-MP bioavailability but not to an extent significant enough to warrant dosage reduction.15 Methotrexate increases 6-MP plasma concentrations slightly, but antagonizes thiopurine metabolite disposition in leukemia blasts resulting in lower thioguanine nucleotide incorporation.56


Adenosine deaminase (ADA) catalyzes the deamination of adenosine to inosine and deoxyadenosine to deoxyinosine. Congenital deficiency of ADA in men leads to lymphocyte dysfunction and severely impaired cellular immunity caused by an accumulation of deoxyadenosine, which is cytotoxic to lymphocytes. The cytotoxic effect of deoxyadenosine on lymphocytes prompted investigators to evaluate adenosine analogs in the treatment of lymphocytic malignancies. Adenosine analogs with documented clinical utility are fludarabine, pentostatin, and cladribine (2′-chlorodeoxyadenosine) (Fig. 9.3). Key pharmacologic features of the adenosine analogs are listed in Tables 9.4, 9.5, 9.6.

Figure 9.3 Structure of adenosine and the adenosine analogs fludarabine (9-arabinofuranosyl-2-fluoroadenosine monophosphate; F-ara-AMP), pentostatin (2-deoxycoformycin), and cladribine (2-chlorodeoxyadenosine).



Fludarabine, a monophosphate analog of adenosine arabinoside (9-β-D-arabinofuranosyl-2-fluoroadenine monophosphate), is resistant to adenosine deaminase with good aqueous solubility allowing intravenous administration57 (Fig. 9.3). Key features of fludarabine are summarized in Table 9.4.




Mechanism of Action

1. Incorporation into DNA as a false nucleotide.

2. Inhibition of DNA polymerase, DNA primase and DNA ligase

3. DNA chain termination


1. Rapid dephosphorylation in plasma to 2-fluoro-ara A (F-ara-A)

2. Activation of F-ara-A to F-ara-ATP (the active metabolite) within cells


1. Rapid dephosphorylation to 2-F-ara A

2. T½ 2-F-ara-A = 6–30 hours in plasma; intracellular t½ of F-ara-ATP = 15 hours


Primarily renal excretion of 2-F-ara-A

Drug interactions

Increases cytotoxicity of cytarabine and cisplatin


1. Myelosuppression

2. Immunosuppression with resulting infections

3. Neurotoxicity at high doses

4. Rare: interstial pneumonitis and hemolytic anemia


Dose reduction needed for patients with renal failure

Mechanism of Action

After intravenous administration, fludarabine is rapidly and completely dephosphorylated in plasma to the nucleoside 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) (Fig. 9.4).58 F-ara-A enters cells via carrier-mediated transport59 and is phosphorylated to its active form, F-ara-ATP. All cytotoxic mechanisms of action of fludarabine require the presence of fludarabine triphosphate (F-ara-ATP).60F-ara-ATP inhibits several intracellular enzymes important in DNA replication including DNA polymerase, ribonucleotide reductase, DNA primase, and DNA ligase I.60, 61 In addition, the monophosphate, F-ara-AMP, is incorporated into DNA. Once incorporated, F-ara-AMP is an effective DNA chain terminator62 primarily at the 3′ end of DNA. The amount of F-ara-AMP incorporated is linearly correlated with loss of clonagenicity. Excision of the 3′-terminal F-ara-AMP does not easily occur, and the presence of this false nucleotide leads to apoptosis.

Although the effects of fludarabine on DNA synthesis account for its activity in dividing cells, fludarabine is also cytotoxicity in diseases with very low growth fractions such as chronic lymphocytic leukemia (CLL) or indolent lymphomas. This raises the question as to how an “S-phase” agent is active in nondividing cells.63 The specific mechanism(s) by which fludarabine induces cell death among quiescent cells is under investigation, but several proposed mechanisms of action include fludarabine's ability to inhibit RNA polymerases by incorporation into RNA, depletion of nicotinamide adenine dinucleotide (NAD) with resultant decrease in cellular energy stores, and interference with normal DNA repair processes.64, 65 The most compelling evidence suggests fludarabine triggers apoptosis after incorporation into DNA during the DNA repair process.65

Figure 9.4 Activation of fludarabine. Fludarabine loses its phosphate group in plasma to fluoro adenine (F-ara-A). F-ara-A enters cells and is phorphorylated to F-ara-ATP, which is the active metabolite. NAD, nicotinamide adenine dinucleotide.

Clinical Pharmacology

Plasma concentrations of parent fludarabine and F-ara-A have been determined using high-performance liquid chromatography.66 Following intravenous administration, parent drug (2-F-ara-AMP) undergoes rapid (2 to 4 minutes) and quantitative conversion to F-ara-A. The rapid conversion of fludarabine to F-ara-A is attributed to the action of 5′nucleotidase present in erythrocytes and endothelial cells. Peak plasma F-ara-A concentrations of 1 to 5 µmol/L are achieved after commonly used doses of 25 to 30 mg/m2 per milligram fludarabine.66, 67 Wide variations in terminal drug half-life (7 to 33 hours) and area under the curve (AUC) are found. Drug clearance is linear, with no change with repeated doses. F-ara-A is excreted primarily in the urine (50 to 60%) with no metabolites detected.60 Among patients with renal impairment, there is a significant decrease in clearance of 2-F-ara-A (ClT = 51.82 ± 6.70 mL/minute per square meter versus 73.53 ± 3.79 mL/minute per square meter) compared with patients with normal kidney function.66, 68 Lichtman et al.68 have proposed that patients with a creatinine clearance (Clcr) of >70 mL/minute per1.73 m2 should receive 25 mg/m2 per day for 5 days of fludarabine, and patients with Clcrof 30 to 70 mL/minute per 1.73 m2 should receive 20 mg/m2 per day for 5 days, and those with Clcrof <30 mL/minute per 1.73 m2 should receive 15 mg/m2per day for 5 days fludarabine.

Oral administration of fludarabine has been evaluated.69 The AUC of F-ara-A increases linearly with increasing dose. Mean bioavailability averages 50 to 55% with large interpatient (30 to 80%), but minimal intraindividual variability. Absorption is not affected by meals.70

The triphosphate (F-ara-ATP) is the major intracellular metabolite of fludarabine and the only metabolite with known cytotoxic activity. Peak F-ara-ATP concentrations in circulating leukemic cells are achieved 4 hours after intravenous fludarabine administration.67 F-ara-ATP has a relatively long intracellular half-life (15 hours), which may account for the efficacy of a daily administration schedule.60 A linear relationship exists between plasma F-ara-A concentrations and intracellular F-ara-ATP in leukemic cells.71


The dose-limiting toxicities of fludarabine are myelosuppression and infectious complications from immunosuppression.57 Toxicity is similar with oral and intravenous preparations.69 Reversible leukopenia and thrombocytopenia have been reported following fludarabine administration with a median time to nadir of 13 days (range, 3 to 25 days) and 16 days (range, 2 to 32 days), respectively. Twenty percent to 50% of treated patients have a neutrophil count nadir less than 1,000/mm3 at standard doses of 25 mg/m2 per day for 5 days. Platelet nadirs of less than 50 to 100,000/mm3 are seen in 20%.72 Myelosuppression is more common when fludarabine is combined with other chemotherapeutic drugs, including rituximab.73 Up to 25% of patients treated with fludarabine will have a febrile episode. Many will be fevers of unknown origin but one-third will have a serious documented infection.

Fludarabine is immunosuppressive. The immunosuppression by fludarabine is associated with inhibition of a key component of signal transduction of lymphocyte activation.74 Therapy is associated with an increased risk of opportunistic infections. CD4 and CD8 T-lymphocytic subpopulations decrease to levels of 150 to 200/mm3 after three courses of therapy.75 Lymphopenia may persist for over 1 year. The most frequent infectious complications are respiratory. Infections with Cryptococcus, Listeria monocytogenesPneumocystis carinii, cytomegalovirus, herpes simplex virus, Varicella zoster, and mycobacterium, organisms associated with T-cell dysfunction, are seen.76 Previous therapy, advanced disease, and neutropenia are risk factors. The incidence of infections complications and grade 3-4 myelosuppression is significantly greater in patients with a creatinine clearance <80 mL/minute, again suggesting dose modifications for patients with renal insufficiency.77 Patient age is not an independent risk factor for fludarabine toxicity.

The development of autoimmune hemolytic anemia has been seen with fludarabine use.78 Hemolysis has been noted following any treatment cycle, but is most common during cycles one through three (71% of cases). Acute tumor lysis is a rare complication in patients with CLL and indolent lymphomas treated with fludarabine.79 Other reported fludarabine toxicities include mild nausea and vomiting, infection, peripheral sensorimotor neuropathy, and hepatocellular toxicity with elevations in serum transaminases. An irreversible neurotoxicity syndrome with cortical blindness, optic neuritis, encephalopathy, generalized seizures, and coma has been described.80 This occurs in patients receiving high drug doses (>40 mg/m2 per d for 5 days). However, mild, reversible neurotoxicity is seen at lower doses with increased frequency and severity with older age. Neurotoxicity is reported in 16% of patients. Pulmonary toxicity characterized by fever, cough, hypoxia, and diffuse interstitial pneumonitis has been reported in 5 to 10% of fludarabine-treated patients.81 Patients with CLL are particularly at risk. Corticosteroid therapy is recommended. Therapy-related myeloid malignancies have been reported in patients receiving the combination of fludarabine and chlorambucil.82

Clinical Use

Fludarabine has demonstrated clinical activity in a variety of low-grade lymphoproliferative malignancies including CLL, hairy-cell leukemia, Waldenstrom's macroglobulinemia, and non-Hodgkin's lymphoma. Response rates from 32 to 57% have been reported among patients with refractory chronic lymphocytic leukemia treated with fludarabine. The median duration of disease control is 65 to 91 weeks. Among patients with previously untreated chronic lymphocytic leukemia, fludarabine has produced responses in more than 70% of patients, including complete responses in one-third. A median survival of 63 months has been reported. In CLL, patients treated with fludarabine have a higher complete response rate (20% versus 4%) than those receiving chlorambucil alone, as well as an increased partial response rate (43% versus 33%). However, no survival difference has been noted.83 Fludarabine has been employed as a component of nonmyeloablative stem cell transplantation for lymphoma.84




Mechanism of Action

1. Inhibits adenosine deaminase with subsequent accumulation of dATP pools

2. Inhibition of DNA replication and repair by dATP




Clearance rate of 8 mL/min/m2, which decreases with decreasing creatinine clearance


Majority of drug is excreted unchanged in the urine

Drug interactions

None recognized


1. Well tolerated at low doses

2. At high doses: nausea, immunosuppression, nephrotoxicity and CNS disturbances


Dose reductions for patients with renal failure

Drug Interactions

Fludarabine is synergistic with cytosine arabinoside. Fludarabine increases intracellular accumulation of ara-C. Increased incorporation of ara-CTP into DNA occurs through modulation of dNTP pools by fludarabine. Fludarabine also acts with ara-C to inhibit DNA polymerase alpha.85

Pentostatin or Deoxycoformycin

Pentostatin or 2′-deoxycoformycin (dCF) is a purine analog originally prepared from a Streptomycin culture but now chemically synthesized. Pentostatin was identified as a potent ADA inhibitor86 and subsequently evaluated as treatment for lymphocytic leukemias. No activity was seen in patients with acute leukemias, but patients with hairy cell leukemia and indolent lymphomas had impressive responses.87 The key pharmacologic features of pentostatin are listed in Table 9.5.


Mechanism of Action

The specific mechanism for pentostatin cytotoxicity is believed to be the result of the accumulation of deoxyadenosine and dATP following ADA inhibition. Pentostatin binds tightly to ADA with a slow dissociation rate of 60 hours.88 Abnormally high levels of deoxyadenosine triphosphate (dATP) achieved following ADA inhibition exert a negative feedback on ribonucleotide reductase, resulting in an imbalance in deoxynucleotide pools. This imbalance slows DNA synthesis and alters DNA replication and repair. S-adenosylhomocysteine hydrolase is also inhibited, blocking normal cellular methylation reactions.87, 88 These mechanisms are relevant to proliferating cells. The mechanism of action of pentostatin on nonproliferating cells is unclear.

Pentostatin enters cells via the nucleoside transport system89 with a rate of cellular uptake that parallels that of other nucleosides. Pentostatin exerts tight-binding inhibition of ADA.86 When administered in doses intended to produce total-body ADA inhibition in ALL, serious renal, pulmonary, and central nervous system toxicity is encountered. Thus, toxicity has limited the usefulness of this drug in conditions associated with high ADA activity, such as acute leukemias. However, pentostatin is active in hairy-cell leukemia, in which cellular ADA levels are lower.90

Clinical Pharmacology

Pentostatin is reasonably stable at neutral pH; however, care must be taken if the drug is extensively diluted with 5% dextrose in water as pentostatin's stability is compromised at pH ≤5.91 Pentostatin has a large volume of distribution with little protein binding.92 The terminal elimination half-life averages 6 hours.93, 94 Plasma levels of pentostatin 1 hour after administration exceed the ADA inhibitory concentration by approximately 106, supporting the recommendation for an intermittent infusion schedule. Only a small amount of pentostatin is metabolized; 40 to 80% of the drug is excreted in urine unchanged within 24 hours.93, 94 Plasma clearance averages 68 mL/minute per square meter and correlates with creatinine clearance. For patients with impaired renal function (creatinine clearance <60 mL/minute), drug half-life is prolonged (approximately 18 hours). Dose reductions are suggested for patients with renal function impairment. Patients with a creatinine clearance >60 mL/minute should receive a dose of 4 mg/m2 every 14 days, patients with Clcr of 41 to 60 mL/minute should receive 3 mg/m2 every 2 weeks, and patients with a Clcrof 20 to 40 mL/minute should receive a 2 mg/m2 dose every 14 days.95 Pentostatin is not orally bioavailable. Pentostatin crosses the blood-brain barrier with CSF concentrations 10 to 13% of serum drug concentrations.96


At commonly used doses (4 mg/m2 every 2 weeks), pentostatin toxicity is modest and therapy is usually well tolerated.97 In a large intergroup trial of 313 patients, grade 3-4 toxicity was uncommon.98 Twenty-two percent of patients treated at 4 mg/m2 every 2 weeks develop grade 3-4 neutropenia. Nausea and vomiting (>grade 3) occurs in 11% of patients. The most common nonmyelosuppressive drug toxicity is nausea (11% of patients at standard doses). Nausea and vomiting may be delayed (12 to 72 hours after administration). Mild-to-moderate lethargy (3% incident), rash, and reactivation of herpes zoster have been reported. Toxicity from higher doses of pentostatin (≥10 mg/m2 per day) includes immunosuppression, conjunctivitis, renal impairment, hepatic enzyme elevation, and central nervous system disturbances.96 Renal toxicity seen in early trials is minimized with the use of lower drug doses and adequate hydration. Nephrotoxicity occurs 10 to 20 days after drug administration. Cardiac complications in older patients have been described but appear to be uncommon.99Patients with poor performance status or impaired renal function have a higher incidence of life-threatening toxicity. An increased risk of opportunistic infections similar to fludarabine and cladribine is seen with pentostatin.100 Initial concerns regarding an increased risk of second malignancies following use of pentostatin have not been confirmed.101

Clinical Use

Pentostatin, delivered in low doses, produces responses in over 90% of patients with hairy-cell leukemia, even those refractory to splenectomy and α-interferon therapy. Estimated disease-free survival at 5 and 10 years is over 85% and 65%, respectively.102 Overall, 5- and 10-year survival is 90% and 80%, respectively.102 Because of its activity in hairy-cell leukemia, pentostatin has also been evaluated in a number of other closely related disorders, including chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, refractory multiple myeloma, and adult T-cell lymphomas. It produces responses, but has no apparent advantage over standard therapies.

Cladribine or 2-Chlorodeoxyadenosine (Leustatin)

Mechanism of Action

Cladribine or 2-chlorodeoxyadenosine is a purine nucleoside analog with antineoplastic activity against low-grade lymphoproliferative diseases, childhood leukemias, and multiple sclerosis. Its important pharmacologic features are noted in Table 9.6.




Mechanism of Action

1. Activation to 2-CdATP that is incorporated into DNA producing DNA strand breaks

2. 2-CdATP inhibits ribonucleotide reductase

3. Triggers apoptosis by activating caspaces


Activation to 2-CdATP within cells


1. Significant variability in cladribine plasma AUC

2. 40–50% oral bioavailability

3. 50% urinary excretion

Drug interactions

Increases toxicity of cytarabine
More frequent rash when used with allopurinol


1. Myelosuppression

2. Fever

3. Immunosuppression with resulting infection complications

4. Rash


Substitution of chlorine at the two position of deoxyadenosine produces 2-chlorodeoxyadenosine or cladribine (2-CdA) (Fig. 9.3), which is relatively resistant to enzymatic deamination by adenosine deaminase. Intracellular transport of 2-CdA occurs via nucleoside delivery mechanisms. Cladribine is a prodrug and requires intracellular phosphorylation for activation. The 5′-triphosphate metabolite (2-chloro-2′-deoxyadenosine 5-triphosphate, 2-CdATP) accumulates in cells rich in deoxycytidine kinase103 (Fig. 9.5). 2-CdATP is incorporated into DNA, producing DNA strand breaks and inhibition of DNA synthesis.104 Cladribine, incorporated into DNA promoter sequences, acts as a transcription antagonist.105 High intracellular concentrations of 2-CdATP also inhibit DNA polymerases106and ribonucleotide reductase,61 causing an imbalance in deoxyribonucleotide triphosphate pools with subsequent impairment of DNA synthesis and repair.

Figure 9.5 Activation of cladribine (2-chorodeoxyadenosine or 2 CdA).

The mechanism for triggering apoptosis in nondividing cells by 2-CdATP is not clear. Cysteine proteases, referred to as caspaces, are active in apoptosis triggered by cladribine.107 2-CdATP interacts with cytochrome C and protease activating factor-1 (PAF-1) to initiate the caspase cascade leading to DNA degradation, even in the absence of cell division.108 Cladribine resistance is most often caused by a deficiency in deoxycytidine kinase.109 P53 mutations110and, to a significantly lesser extent, the presence of multidrug resistance protein 4,111 also result in resistance to cladribine.

Clinical Pharmacology

Liquid chromatography is used to quantify cladribine and its primary metabolite, 2-chlorodeoxyadenosine.112 Cladribine is a prodrug. It is activated within the cell to cladribine nucleotides. Intracellular drug concentrations are several hundred-fold higher than plasma concentrations.113 Cladribine nucleotides are retained in leukemic cells with a intracellular half-life of 9 to 30 hours. The long intracellular half-life supports the use of intermittent drug administration.114Unfortunately, no correlations have been found between the plasma AUC of cladribine or intracellular cladribine concentrations and the response to treatment.115

Following a 2-hour infusion of 0.12 mg/kg cladribine, peak serum concentrations of nearly 50 µg/mL are achieved.114 A linear dose-concentration relationship is present up to doses of 2.5 mg/m2 per hour. Cladribine clearance rates of 664 to 978 mL/hr per kilogram have been reported with significant interpatient variability (±50%). The drug is weakly bound to plasma protein (20%). Renal clearance accounts for 50% of total drug clearance, with 20 to 30% of drug excreted as unchanged cladribine within the first 24 hours.114, 116 Little information is available regarding dose adjustments for renal or hepatic insufficiency. However, given the high renal drug clearance, caution should be taken in using cladribine in patients with renal failure. Chloroadenine is the major metabolite formed. Renal excretion of chloroadenine accounts for clearance of 3% of administered cladribine.114

Bioavailability of subcutaneously administered cladribine is excellent (100%).117 Oral administration has been evaluated with bioavailability of 40 to 50%. Increased metabolism to chloroadenine is seen following oral administration suggesting a first-pass effect.112, 117 Significant patient-to-patient variability (±28%) exists in the AUC achieved following administration of drug by any method.114, 116


Cladribine's dose-limiting toxicity using a standard dosage of 0.7 mg/kg per cycle (usually as a continuous 7-day infusion at 0.1 mg/m2 per day) is myelosuppression.118 Nausea, alopecia, hepatic and renal toxicity rarely occur at this dose. Fever (temperature >100°F) is seen in two-thirds of patients treated with cladribine, mostly during the period of neutropenia. Myelosuppression and immunosuppression with development of opportunistic infections are the major adverse events.100, 119 Severe (grade 3-4) neutropenia and lymphopenia occur in half of treated patients. Neutrophil counts decrease 1 to 2 weeks after starting therapy and persist for 3 to 4 weeks.119 Twenty percent of patients develop grade 3-4 thrombocytopenia. Infections occur in 15 to 40% of patients, often opportunistic infections, such as Candida or Aspergillis. Betticher et al.120 have found that reducing the dose of 2CdA from 0.7 to 0.5 mg/kg per cycle decreases the grade 3 myelosuppression rate (33 to 8%) and the infection rate (30 to 7%) without a change in response rate.

Toxicities other than myelosuppression and infections are rare, but have been reported. Following high dose 2CdA (5 to 10 times the recommended therapeutic dose), renal failure, and motor weakness has been described. Autoimmune hemolytic anemia has been reported in patients with CLL who are receiving cladribine.121 Eosinophilia, nausea, and fatigue have been noted.

Clinical Use and Drug Interactions

Cladribine's spectrum of activity is similar to other adenosine analogs (e.g., fludarabine). Patients with CLL, hairy-cell leukemia, low-grade non-Hodgkin's lymphomas, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia systemic mastocytosis, and blast-phase chronic myelogenous leukemia have responded to cladribine therapy.122, 123 Subcutaneous and oral routes of drug administration have demonstrated activity.124 A drug-drug interaction between cladribine and cytarabine has been reported. Pretreatment of patients with cladribine increases the intracellular accumulation of ara-CTP, the active metabolite of cytarabine, by 40%.125 An increased frequency of drug rash has been noted when cladribine and allopurinol have been used concomitantly.126


Allopurinol has no antineoplastic activity. However, it is frequently used in patients with leukemia and lymphoma to prevent hyperuricemia and uric acid nephropathy. The clinical use of allopurinol in cancer chemotherapy and its potential interactions with various antitumor agents are summarized in this section. The key features of allopurinol are summarized in Table 9.7.

Mechanism of Action

Allopurinol (4-hydroxpyrazolo [3,4-d] pyrimidine) and its major metabolic product oxipurinol (4,6-dihydroxpyrazolo [3,4-d] pyrimidine) are analogs of hypoxanthine and xanthine, respectively. Both inhibit the enzyme xanthine oxidase and block the conversion of hypoxanthine and xanthine to uric acid (Fig. 9.6). Allopurinol binds to xanthine oxidase and undergoes internal conversion to oxipurinol, simultaneously reducing xanthine oxidase.127 Oxipurinol inhibits xanthine oxidase by attaching at the active site of the enzyme in a stoichiometric fashion, one molecule of oxipurinol for each functionally active site of xanthine oxidase (KI = 5.4 × 10-10M).

Allopurinol reduces serum uric acid concentrations not only by inhibiting xanthine oxidase but also by decreasing the rate of de novo purine biosynthesis. Administration of allopurinol to patients with primary gout causes an increase in serum xanthine and hypoxanthine concentrations.128 Increased conversion of hypoxanthine to inosinic acid and subsequently to adenylic and guanylic acid occurs (Fig. 9.7). Adenylic and guanylic acid are allosteric inhibitors of 5′phosphoribosyl-1-pyrophosphate (PRPP) aminotransferase, the critical enzyme involved in de novo purine synthesis. Total purine excretion (xanthine plus hypoxanthine plus uric acid) decreases by 30 to 40% after initiation of allopurinol therapy. Allopurinol and oxipurinol are also converted to their respective ribonucleotides. This leads to decreased intercellular concentrations of PRPP, which also contributes to decreased purine synthesis.129 The effect of allopurinol on de novo purine synthesis is negligible in treatment of the tumor lysis syndrome, in which release of purines from DNA occurs.




Mechanism of Action

1. Limits conversion of xanthine and hypoxanthine to uric acid by inhibiting xanthine oxidase.

2. Causes feedback inhibition of de novo purine synthesis.


Rapid metabolic conversion to oxipurinol, which is the active metabolite


Allopurinol t½: 0.7–1.6 hr
Oxipurinol t1/2: 14–28 hr


Allopurinol - metabolism to oxipurinol
Oxipurinol - renal excretion

Drug Interactions

1. Prolongs half-life of 6-MP and azathioprine by decreasing rate of metabolic elimination.

2. May impair hepatic microsomal enzyme function.


1. Rash

2. Hypersensitivity syndrome (TEN, renal failure, liver, hepatic failure)

3. Rare: xanthine nephropathy


1. Reduce doses of 6-MP or azathioprine.

2. Reduce allopurinol doses for renal insufficiency.

3. Stop drug for rash.

Figure 9.6 Metabolic pathway for the conversion of hypoxanthine and xanthine to uric acid and of allopurinol to oxipurinol.

Clinical Pharmacology

Allopurinol is available in 100- and 300-mg tablets and as an intravenous preparation.130 Allopurinol is well absorbed orally (50 to 80% bioavailability).131After oral administration of 300 mg allopurinol, plasma oxipurinol concentrations of 10 to 40 µM (1.5 to 6.5 mg/L) are achieved within 1 to 3 hours.132Intravenous allopurinol achieves maximal plasma concentrations within 30 minutes. Kinetics of the active metabolite, oxipurinol, are similar following intravenous or oral administration.

Figure 9.7 Feedback inhibition of de novo purine biosynthesis. Inhibition of xanthine oxidase by allopurinol causes an increase in serum hypoxanthine concentrations, which in turn causes increased concentrations of inosinic, xanthylic, adenylic, and guanylic acids. Guanylic and adenylic acids are inhibitors of phosphoribosylpyrophosphate aminotransferase (PRPP- aminotransferase), the initial step in de novo purine synthesis.


The plasma half-life of allopurinol is short (30 to 100 minutes) with rapid conversion of allopurinol to oxipurinol. The volume of distribution of both allopurinol and oxipurinol is roughly that of total body water with little binding of either drug to plasma proteins. A small amount of allopurinol is excreted directly in the urine (clearance rate, 13 to 19 mL/minute), but most of an administered dose of allopurinol is metabolized to oxipurinol. In patients with normal renal function, steady-state oxipurinol plasma concentrations are 15 mg/L (100 µM) at an allopurinol dose of 300 mg/day. This is in excess of the concentration needed to inhibit xanthine oxidase (25 µM). Impaired renal clearance of oxipurinol leads to a prolonged oxipurinol plasma half-life (14 to 28 hours).133Oxipurinol clearance and drug half-life are closely tied to creatinine clearance. Patients with renal failure have delayed oxipurinol excretion and require a dose reduction to prevent drug accumulation. Maintenance doses of allopurinol should be reduced to maintain serum oxipurinol levels comparable with those in patients with normal renal function.133, 134 Older patients (>70 years) have reduced oxipurinol clearance related to an age-dependent decline in renal function.135


Allopurinol therapy is well tolerated in most patients and produces few side effects. Skin rash is seen in 2% of patients taking allopurinol.136 In patients allergic to allopurinol, oxipurinol may be tried as an alternative therapy for xanthine oxidase inhibition. However, cross-sensitivity between allopurinol and oxipurinol has been noted. In patients allergic to allopurinol, the drug should be avoided, if possible. However, desensitization to allopurinol has been successfully employed in allergic patients for whom no substitute is available.137 Gastrointestinal intolerance, fever, and alopecia are rare complications of allopurinol therapy. A severe, potentially life-threatening hypersensitivity syndrome resulting from allopurinol use has been reported.133, 138 Patients usually have fever (87% of reported cases), eosinophilia (73%), skin rash (92%) including toxic epidermal neurolysis, renal dysfunction, and hepatic failure (68%). Death has been reported in 21% of published cases. This hypersensitivity syndrome usually appears 2 to 4 weeks after the initiation of 300 to 400 mg/day allopurinol. Over 80% of patients developing this syndrome have underlying renal failure when allopurinol therapy is started. Steady-state concentrations of oxipurinol are elevated in this situation and may play a role in the development of the toxicity syndrome. It is hoped that adjustments of allopurinol doses for renal insufficiency will lower the risk for drug toxicity.133

Xanthine nephropathy is a rare complication of allopurinol therapy in cancer patients.139 Even though xanthine precipitation is a potential complication of allopurinol therapy in patients who have massive tumor lysis, allopurinol treatment is beneficial to such patients. It enables them to excrete a larger total purine load. Because the solubility of a single purine, such as xanthine, hypoxanthine, or uric acid, is independent of the others, dividing the purine load among these three purines by the use of allopurinol will increase the total amount of purine that can be excreted in the urine. Xanthine concentrations in excess of 5 mg/dL may cause a falsely low uric acid measurement as determined by the uricase method.140 Elevated xanthine concentrations do not affect uric acid measurements determined by the phosphotungstate colorimetric assay.

Clinical Uses and Drug Interactions

In the treatment of primary gout, allopurinol produces a fall in serum uric acid concentration and a decrease in urinary uric acid excretion 1 or 2 days following initiation of therapy and produces a maximal reduction in serum urate levels within 4 to 14 days. A once-daily dose of 300 mg of allopurinol is clinically as effective as three equally divided doses of 100 mg.141 In patients who do not respond to 300 mg of allopurinol per day, dosages of 600 to 1,000 mg/day are usually effective in lowering serum uric acid concentrations.

With rapid tumor lysis following cancer treatment, there is a sudden rise in serum uric acid caused by cell destruction with release of preformed purines from degraded DNA. The rapid release of uric acid can result in renal failure because of the precipitation of urate crystals in the distal renal tubules where concentration and acidification are maximal. The development of hyperuricemia after treatment of many leukemias and lymphomas is so common that hydration and allopurinol therapy are recommended before chemotherapy for these diseases is begun. Doses of 300 mg to 400 mg/m2 per day should be given for 2 to 3 days, with subsequent doses reduced to 300 to 400 mg/day. These doses prevent marked increases in uric acid excretion after chemotherapy,142, 143 although clinically significant tumor lysis is still seen in 5% of patients with high-grade lymphomas and laboratory evidence of lysis in 40%.

Xanthine oxidase catalyzes the conversion of both azathioprine and 6-MP to the inactive metabolite, 6-thiouric acid. Oral doses of 6-MP or azathioprine should be reduced by at least 65 to 75% when allopurinol is concomitantly used. White blood cell counts should be monitored frequently. Even with azathioprine dose reductions of 67%, myelosuppression is seen in over one-third of patients also treated with allopurinol.144


1. Burchenal JH, Murphy ML, Ellison RR, et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood 1953;8:965–999.

2. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992;43:329–339.

3. Tidd DM, Patterson ARP. Distinction between inhibition of purine nucleotide synthesis and the delayed cytotoxic reaction of 6-mercaptopurine. Cancer Res 1974;34:733–737.

4. Waters TR, Swann PF. Cytotoxic mechanism of 6-thioguanine: L Mut S, the human mismatch binding heterodimer binds to DNA containing S6-methythioguanine. Biochemistry 1997;36: 2501–2506.

5. Swann PF, Waters TR, Moulton DC, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 1996;273:1109–1011.

6. Dervieux T, Blanco JG, Krynetcki EY, et al. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Research 2001;61:5810–5816.

7. Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatic damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol 1986;35: 3533–3541.

8. Pan BF, Nelson JA. Characterization of the DNA damage in 6-thioguanine treated cells. Biochem Pharmacol 1990;40: 1063–1069.

9. Erb N, Harms DO, Janka-Schaab G. Pharmacokinetics and metabolism of thiopurines in children with ALL receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 1998;42: 266–272.

10. Tiede I, Fritz G, Stand S, et al. C28-dependent RAC activation is the molecular target of azathioprine in primary human CD4 T lymphocytes. J Clin Invest 200;111:1133–1145.

11. Lavi L, Holcenberg JS. A rapid sensitive high performance liquid chromatography assay for 6-mercaptopurine metabolites in red blood cells. Anal Biochem 1985;144:514–521.

12. Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in ALL being optimally delivered? N Eng J Med 1983;308:1005–1009.

13. Arndt CAS, Balis FM, McCully CL, et al. Bioavailability of low-dose vs high-dose 6-mercaptopurine. Clin Pharmacol Ther 1988;43:588–591.

14. Jacqz-Aigrain E, Nafa S, Medard Y, et al. Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia. Eur J Clin Pharmacol 1997;53:71–74.

15. Balis FM, Holcenberg JS, Zimm, S et al. The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther 1987;41:384–387.

16. Balis FM, Holcenberg JS, Poplack DG, et al. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk ALL; a joint Children's Cancer Group and Pediatric Oncology Branch study. Blood 1998;92: 3569–3577.

17. Zimm S, Collins JM, O'Neill D, et al. Chemotherapy: Inhibition of first-pass metabolism in cancer interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 1983;34:810–817.

18. Zimm S, Ettinger LJ, Holcenberg JS, et al. Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 1985;45:1869–1873.

19. Lafolie P, Hayder S, Bjork O, et al. Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with ALL. Eur J Clin Pharmacol 1991;40: 599–601.

20. Burton NK, Barnett MJ, Aherne GW, et al. The affect of food on the oral administration of 6-mercaptopurine. Cancer Chemother Pharmacol 1986;18:90–91.

21. Burton NK, Aherne GW. The effect of cotrimoxazole on the absorption of orally administered 6-mercaptopurine in the rat. Cancer Chemother Pharmacol 1986;16:81–84.

22. Weinshilboum RM. Methyltransferase pharmacogenetics. Pharmacol Ther 1989;43:77–90.

23. Holme SA, Duley JA, Sanderson J. Erythrocyte thiopurine methyl transferase assessment prior to azathioprine use in the UK. QJM 2002;95:439–444.

24. Coulthard SA, Howell C, Robson J, Hall AG. The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia. Blood 1998;92: 2856–2862.

25. Lennard L, VanLoon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989;46:149–154.

26. Jones CD, Smart C, Titus A, et al. Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther 1993;53:348–353.

27. Koren G, Ferrazini G, Sulh H, et al. Systemic exposures to mercaptopurine as a prognostic factor in acute lymphocytic leukemia. N Engl J Med 1990;323:17–21.

28. Hayder S, Lafolie P, Bjork O, et al. 6-Mercaptopurine plasma levels in children with acute lymphoblastic leukemia: Relationship to relapse risk and myelotoxicity. Ther Drug Monit 1989; 11:617–622.

29. Lennard L, Lilleyman JS. Variable 6-mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989;7:1816–1823.

30. Lennard L, Lilleyman JS, Van Loon JA, et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukemia. Lancet 1991;336:225–229.

31. Otterness D, Szumlanski C, Lennard L, et al. Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms. Clin Pharmacol Ther 1997;62:60–73.

32. Evans WE. Thiopurine 5-methyltransferase: a genetic polymorphism that affects a small number of drugs in a big way. Pharmacogenetics 2002;12:421–423

33. Tai HL, Krynetski EY, Yates CR, et al. Thiopurine 5-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996;58:694–702.

34. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine 5-methylltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997;126:608–614.

35. LePage GA, Whitecar JP. Pharmacology of 6-thioguanine in man. Cancer Res 1971;31:1627–1631.

36. Brox LW, Birkett L, Belch A. Clinical pharmacology of oral thioguanine in acute myelogenous leukemia. Cancer Chemother Pharmacol 1981;6:35–638.

37. Kitchen BJ, Balis FM, Poplack DG, et al. A pediatric Phase I trial and pharmacokinetic study of thioguanine administered by continuous i.v. infusion. Clin Cancer Res 1997;3:713–717.

38. Liliemark J, Petterson B, Lafolie P, et al. Determination of plasma azathioprine and 6-mercaptoprine in patients with rheumatoid arthritis treated with oral azathioprine. Ther Drug Monit 1990;12:339–343.

39. Chan CLC, Erdmen GR, Gruber SA, et al. Azathioprine metabolism: Pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients. J Clin Pharm 1990;30:358–363.

40. Evans WE, Hon YY, Bomgaars, L et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001;19:2293–2301.

41. Schwab M, Schaffeler E, Marx C, et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine 5-methyltranferase polymorphism. Pharmacogenetics 2002;12:429–436.

42. Einhorn M, Davidson I. Hepatotoxicity of 6-mercaptopurine. JAMA 1964;188:802–806.

43. Gearry RB, Barclay ML, Burt MJ, et al. Thiopurine 5-methltransferase (TPMT) gene type does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Alimentary Pharmacol Ther 2003;18:395–400.

44. Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther 2004;75:274–281.

45. Duttera MJ, Caralla RL, Gallelli JF. Hematuria and crystalluria after high-dose 6-mercaptopurine administration. N Eng J Med 1972;287:292–294.

46. Polifka JE, Friedman, JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology 2002;65:240–261.

47. Francella A, Dyan H, Bodian C, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003;124:9–17.

48. Kovach JS, Rubin J, Creagan ET, et al. Phase I trial of parenteral 6-thioguanine given on 5 consecutive days. Cancer Res 1986;46: 5959–5962.

49. Gill RA, Onstad GR, Cardmore JM, et al. Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med 1982;96:58–60.

50. Fields CK, Robinson JW, Roy TM, et al. Hypersensitivity reaction to azathioprine. South Med J 1998;91:471–474.

51. Silman AJ, Petrie J, Hazelman B, et al. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: A 20 year follow-up study. Ann Rheum Dis 1988;47:988–992.

52. Kwong AL, Au WY, Liang RH. Acute myeloid leukemia after azathioprine treatment for autoimmune disease association with -7/7q-. Cancer Genetics and Cytogenetics 1998;104:94–97.

53. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998;129:716–718.

54. Lennard L, Welch JC, Lilleyman JS. Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity. Br J Clin Pharmacol 1997;44:455–461.

55. Kennedy DT, Hayney MS, Lake KD. Azathioprine and allopurinol: the price of an avoidable drug interaction. Ann Pharmacothera 1996;30: 951–954.

56. Dervieux T, Hancock ML, Pui CH, et al. Antagonism by methotrexate on mercaptopurine disposition in lymphoblastic during upfront treatment of acute lymphoblastic leukemia. Clin Pharmacol Ther 2003;73:506–516.

57. Adkins JC, Peters DH, Markham A. Fludarabine. An update of its pharmacology and use in the treatment of haematological malignancies. Drugs 1997;53:1005–1037.

58. Danhauser L, Plunkett W, Keating M, et al. 9-B-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma. Cancer Chemother Pharmacol 1986;18:145–152.

59. Molina-Arcas M, Bellosillo B, Casado FJ, et al. Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood 2003;101:2328–2334.

60. Gandhi V, Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 2002;41:93–103.

61. Parker WB, Ashok RB, Shen SX, et al. Interaction of the 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerase, DNA primase and ribonucleotide reductase. Mol Pharmacol 1988;34:485–489.

62. Kamiya K, Huang P, Plunkett W. Inhibition of the 3′→ 5′ exonucleases of human DNA polymerase epsilon by fludarabine- terminated DNA. J Biol Chem 1996;271:19428–19435.

63. Plunkett W, Begleiter A, Liliemark O, et al. Why do drugs work in CLL? Leuk Lymphoma 1996;22(Suppl 2):1–11.

64. Pettitt A. Mechanism of action of purine analogs in chronic lymphocytic leukaemia. Br J Hematol 2003;121:692–702.

65. Sandoval A, Consoli U, Plunkett W. Fludarabine-mediated inhibition of nucleotide excision repair induces apoptosis in quiescent human lymphocytes. Clin Cancer Res 1996;2:1731–1741.

66. Malspeis L, Grever MR, Staubus AE, et al. Pharmacokinetics of 2-F-ara-A (9-B-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Sem Oncol 1990;17(Suppl 8):18–32.

67. Danhauser L, Plunkett W, Liliemark J, et al. Comparison between the plasma and intracellular pharmacology of 1-(-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate in patients with relapsed leukemia. Leukemia 1987;1:638–643.

68. Lichtman SM, Etcubanas E, Budman D, et al. The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a perspective dose adjustment study. Cancer Invest 2002;20:904–913.

69. Posker GL, Figgitt DP. Oral fludarabine. Drugs 2003;63: 2317–2323.

70. Oscier D, Orchard JA, Culligan D, et al. The bioavailability of oral fludarabine phosphate is unaffected by food. Hematol J 2001;2:316–321.

71. Gandhi V, Estey E, Du M, et al. Maximum dose of fludarabine for maximal modulation of arabinosyl -cytosine triphosphate in human leukemic blast cells during therapy. Clin Cancer Res 1997;3:1539–1545.

72. Sorensen JM, Vena DA, Fallavollita A, et al. Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report. J Clin Oncol 1997;15:458–465.

73. Byrd JC, Peterson BL, Morrison VA, et al. Randomized Phase II study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic untreated patients with B-cell chronic lymphocytic leukemia: results from the CALGB 9712. Blood 2003;101:6–14.

74. Frank DA, Mahajan S, Ritz J. Fludarabine-induced immunosuppression is associated with inhibitor of STAT 1 signaling. Nat Med 1999;5:444–447.

75. 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 1998;92:1165–1171.

76. Anaissie EJ, Kontoyiannis DP, O'Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 1998;129:559–566.

77. Mortell RE, Peterson BL, Cohen HJ, et al. Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia. Chemother Pharmacol 2002; 50:37–45.

78. Weiss RB, Freiman J, Kweder SL, et al. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998;16:1885–1889.

79. Cheson BD, Frame JN, Vena D, et al Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 1998;16:2313–2320.

80. Cheson BD, Vena DA, Foss FM, et al. Neurotoxicity of purine analogs: a review. J Clin Oncol 1994;12:2216–2228.

81. Helman DL, Byrd JL, Alex NC, et al. Fludarabine-related pulmonary toxicity: a distinct clinical entity in chronic lymphoproliferative syndromes. Chest 2002;127:785–790.

82. Morrison VA, Rai KR, Peterson BL, et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil; results of an inter group study: Cancer and Leukemia Group B 9011. J Clin Oncol 2002;20:3878–3884.

83. Rai K, Peterson B, Applebaum F, et al. Fludarabine compared with chlorambucil as primary therapy for active chronic lymphocytic leukemia. N Engl J Med 2000;343:1750–1757.

84. Khouri IF, Champlin RE. Nonmyeloablative stem cell transplantation for lymphoma. Sem Oncol 2004;31:22–26.

85. Gandhi V, Huang P, Chapman AJ, et al. Incorporation of fludarabine and 1-beta-D-arabinofuranosylcytosine 5′-triphosphates by DNA polymerase alpha: affinity, interaction and consequences. Clin Cancer Res 1997;3:1347–1355.

86. Agarwal RP. Inhibitors of adenosine deaminase. Pharmacol Ther 1982;17:399–429.

87. O'Dwyer PJ, Wagner B, Leyland-Jones B, et al. 2′-Deoxycoformycin (Pentostatin) for lymphoid malignancies. Ann Intern Med 1988;108:733–743.

88. Jackson RC, Leopold WR, Ross DA. The biochemical pharmacology of (2′R)-chloropentostatin, a novel inhibitor of adenosine deaminase. Adv Enzyme Regul 1986;25:125–139.

89. Wiley JS, Smith CL, Jamieson GP. Transport of 2′deoxycoformycin in human leukemic and lymphoma cells. Biochem Pharmacol 1991;42:708–710.

90. Johnston JB, Glazer RI, Pugh L, et al. The treatment of hairy-cell leukaemia with 2′-deoxycoformycin. Br J Haematol 1986;63: 525–534.

91. Al-Razzak KA, Benedetti AE, Waugh WN, et al. Chemical stability of pentostatin (NSC-218321), a cytotoxic and immunosuppressant agent. Pharmaceutical Res 1990;7:452–460.

92. Kane BJ, Kuhn JG, Roush MK. Pentostatin: an adenosine deaminase inhibitor for the treatment of hairy cell leukemia. Ann Pharmacother 1992;26:939–946.

93. Smyth JF, Paine RM, Jackman AL, et al. The clinical pharmacology of the adenosine deaminase inhibitor 2′deoxycorformycin. Cancer Chemother Pharmacol 1980;5: 93–101.

94. Major PP, Hgarwal RP, Kufe DW. Clinical pharmacology of deoxycoformycin. Blood 1981;58:91–96.

95. Lathia C, Fleming G, Mayer M, et al. Pentostatin pharmacokinetics and dosing recommendations in patients with mild renal impairment. Cancer Chemother Pharmacol 2002;50:121–126.

96. Major PP, Agarwal RP, Kufe DW. Deoxycoformycin: neurological toxicity. Cancer Chemother Pharmacol 1981;5:193–196.

97. Margolis J, Grever MR. Pentostatin; Nipent: a review of potential toxicity and its management. Sem Oncol 2000;27(Suppl)5:9–14.

98. Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon alfa 2A in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13:974–982.

99. Grem JL, King SA, Chun HG, et al. Cardiac complications observed in elderly patients following 2′deoxycoformycin therapy. Am J Hematol 1991;38:245–247.

100. Samonis G, Kontoyiannis DP. Infectious complications of purine analog therapy. Current Opin Infect Disease 2001; 14:409–413.

101. Cheson BD, Vena DA, Barrett J, et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999;17:2454–2460.

102. Flinn IW, Kopecky KJ, Foucar MK, et al. Long-term follow-up of remission duration mortality and second malignancy in hairy cell leukemia patients treated with pentostatin. Blood 2000;96: 2981–2986.

103. Kawasaki H, Carrera CJ, Piro LO, et al. Relationship of deoxycytidine kinase and cytoplasmic 5′ nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine. Blood 1993;81: 597–601.

104. Seto S, Carrera CJ, Kubota M, et al. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 1985;75:377–383.

105. Hartman WR, Hantosh P. The antileukemic drug 2-chlorodeoxyadenosine: an intrinsic transcription antagonist. Mol Pharmacol 2004;65:227–234.

106. Hentosh P, Kools R, Blakley RL. Incorporation of 2-halogen-2′- deoxyadenosine 5-triphosphosphates into DNA during replication by human polymerases alpha and beta. J Bio Chem 1990;265:4033–4040.

107. Ceruti S, Beltrami E, Matarrese P, et al. A key role for caspase-2 and caspase-3 in apoptosis induced by 2′chloro-2-deoxyadenosine (cladribine) and 2-chloro adenosine in human astrocytoma cells. Mol Pharmacol 2003;63:1437–1447.

108. Leoni LM, Chao Q, Cottam HB, et al. Induction of an apoptotic program in cell free extracts by 2-chloro-2′deoxyadenosine 5′ triphosphate and cytochrome C. Proc Natl Acad Sci U S A 1998;95:9567–9571.

109. Mansson E, Spaskoukoskaja T, Sallstrom, J et al. Molecular and biochemical mechanisms of fludarabine and cladribine resistance in a human promyelocytic cell line. Cancer Res 1999; 59:5956–5963.

110. Galnarini CM, Voorzanger N, Faletten N, et al. Influence of P53 and P21 (WAFI) expression on sensitivity of cancer cells to cladribine. Biochem Pharmacol 2003:65:121–129.

111. Reid G, Wielinga P, Zelcer N, et al. Characterization of the transporter of nucleoside analog drugs by the human multidrug resistant proteins MRP4 and MRP5. Sem Oncol 2003;30:243–247.

112. Lindemalm S, Lilemark J, Julinsson G, et al. Cytotoxicity and pharmacokinetic of cladribine metabolite 2-chloroadenine in patients with leukemia. Cancer Lett 2004;210:171–177.

113. Liliemark J, Juliusson G. Cellular pharmacokinetics of 2-chloro-2′-deoxyadenosine nucleotides: comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients. Clin Cancer Res 1995; 1:385–390.

114. Liliemark J. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet 1997;32:120–131.

115. Albertioni F, Lindemalm S, Reichelova V, et al. Pharmacokinetics of cladribine and its 5′monophosphate and 5′ triphosphate in leukemic cells of patients with chronic lymphocytic leukemia. Clin Cancer Res 1998;4:653–658.

116. Kearns CM, Blakley RL, Santana VM, et al. Pharmacokinetics of cladribine (2-chlorodeoxyadenosine) in children with acute leukemia. Cancer Res 1994;54:1235–1239.

117. Lilliemark J, Albertioni F, Hansen M, et al. On the bioavailability of oral and subcutaneous 2-chloro2′-deoxyadenosine in humans: alternative routes of administration. J Clin Oncol 1992;10: 1514–1518.

118. Piro LD, Carrera CJ, Carson DA, et al. Lasting remission in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990;322: 1117–1121.

119. Cheson BD. Infectious and immunosuppressive complications of purine analog therapy. J Clin Oncol 1995;13:2431–2448.

120. Betticher DC, von Rohr A, Ratschiller D, et al. Fewer infections, but maintained antitumor activity with lower-dose vs standard-dose cladribine in pretreated low-grade non-Hodgkin's lymphoma. J Clin Oncol 1998;16:850–858.

121. Chasty RC, Myint H, Oscier DG, et al. Autoimmune haemolysis in patients with B-CLL treated with chlorodeoxyadenosine (CDA). Leuk Lymphoma 1998;29:391–398.

122. Saven A, Lemon RH, Kosty M, et al. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol 1995;13:570–574.

123. Byrd JC, Peterson B, Piro L, et al. A Phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia. Results form CALGB study q9211. Leukemia 2003; 17:323–327.

124. Juliusson G, Christiansen I, Hansen MM, et al. Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia. J Clin Oncol 1996;14:2160–2166.

125. Crews KR, Gandhi V, Srivostava DK, et al. Interim comparison of a continuous infusion versus a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. J Clini Oncol 2002;20:4217–4224.

126. Chubar Y, Bennett M. Cutaneous reations in hairy cell leukemia treated with 2-chlorodeoxyadenosine and allopurinol. Br J Hematol 2003;122:768–770.

127. Spector T. Inhibition of urate production by allopurinol. Biochem Pharmacol 1977;26:355–358.

128. Caskey CT, Ashton DM, Wyngaarden JB. Enzymology of feedback inhibition of glutamine phosphoribosylpyrophosphate aminotransferase by purine ribonucleotide. J Biol Chem 1964; 239:2570–2579.

129. Fox IH, Wyngaarden JB, Kelley WN. Depletion of erythrocyte phosphoribosylpyrophosphate in man; a newly observed effect of allopurinol. N Engl J Med 1970;283:1177–1182.

130. Smalley RV, Guaspari A, Haase-Statz S, et al. Allopurinol:intravenous use for prevention of hyperuricemia. J Clin Oncol 2000;18:1758–1763.

131. Guerra P, Frias J, Ruiz B, et al. Bioequivalence of allopurinol and its metabolite oxipurinol in two tablet formulations. Pharm Ther 2001;26:113–119.

132. Hande KR, Reed E, Chabner BA. Allopurinol kinetics. Clin Pharmacol Ther 1978;23:598–605.

133. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity; description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76:47–56.

134. Kumar A, Edward N, White MI, et al. Allopurinol, erythema multiform and renal insufficiency. BMJ 1996;312:173–174.

135. Turnheim K, Krivanek P, Oberbauer R. Pharmacokinetics and pharmacodynamices of allopurinol in elderly and young subjects. Br J Clin Pharmacol 1999;48:501–509.

136. Boston Collaborative Drug Surveillance Program. Excess of ampicillin rash associated with allopurinol or hyperuricemia. N Engl J Med 1972;286:505–507.

137. Fam AG, Lewtas J, Stein J, et al. Desensitization to allopurinol in patients with gout and cutaneous reactions. Am J Med 1992; 93:299–302.

138. Plum HJ, van Deuren M, Wetzels JFM. The allopurinol hypersensitivity syndrome. Neth J Med 1998;52:107–110.

139. Green ML, Fujimoto WY, Seegmiller JE. Urinary xanthine stones - a rare complication of allopurinol therapy. N Engl J Med 1969;280:426–427.

140. Hande KR, Perini R, Putterman G, et al. Hyperxanthinemia interferes with serum uric acid determinations by the uricase method. Clin Chem 1979;25:1492–1494.

141. Rodnan GP, Robin JA, Tolchin SF, et al. Allopurinol and gouty hyperuricemia. JAMA 1975;231:1143–1147.

142. Feusner J, Farber MS. Role of intravenous allopurinol in the management of acute tumor lysis syndrome. Sem Oncol 2001;285:13–18

143. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkins lymphoma. Am J Med 1993;94: 133–139.

144. Cummins D, Sekar M, Halil O, et al. Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. Transplantation 1996;61:1661–1662.