Purine Antagonists

These purine analogues, similar to their pyrimidine counterparts, require metabolic conversion before activation, which results in inhibition of de novo purine synthesis, and are consequently incorporated into DNA. Some also inhibit DNA polymerase and ribonucleotide reductase. These drugs enter cells via the nucleoside transport system. Myelosuppression is the major toxicity shared by all these agents.

6-Mercaptopurine and Thioguanine

6-Mercaptopurine (6-MP) and thioguanine (6-TG) are analogues of hypoxanthine and guanine, respectively, wherein there is a substitution of a sulfhydryl group for the endogenous 6-OH position. Both are intracellularly anabolized through the hypoxanthine-guanine phosphoribosyl trans-ferase (HGPRT) pathway to form 6-thioinosine monophosphate (TIMP) and 6-thioguanylic acid (TGMP), respectively, which inhibit de novo purine synthesis mediated by 5-phosphoribosyl-1 pyrophosphate (PRPP) amidotransferase. Cytotoxicity arises from the incorporation of 6-thioguanosine triphosphate (6-TGTP) and the deoxytriphosphate form into DNA and RNA, which triggers the mismatch repair pathway leading into apoptosis. In spite of these similarities, cross-resistance between these two agents is not complete, as 6-TG remains active in HGPRT-deficient cells resistant to 6-MP.91

Both 6-MP and 6-TG are converted to inactive metabolites by the enzyme thiopurine methyltransferase (TPMT), with 6-TG being more extensively S-methylated than 6-MP. Genetic polymorphisms in the TPMT gene associated with reduced enzyme activity have been described. 6-TG is also inactivated upon deamination by the enzyme guanase. 6-MP, unlike 6-TG, is catabolized by xanthine oxidase, high concentrations of which can be found n the intestinal mucosa and liver. Both 6-MP and 6-TG have poor and variable oral bioavailability that is further reduced with food intake. In the case of 6-MP, this arises from the large first-pass effect as the drug is metabolized by xanthine oxidase. Allopurinol, a xanthine oxidase inhibitor, prevents catabolism of 6-MP. Moreover, concomitant allopurinol intake increases 6-MP bioavailability fivefold.92 Dose reduction of 6-MP is thus warranted in patients taking allopurinol.

Anorexia, nausea, and vomiting may occur, especially among adults, more commonly with 6-MP than 6-TG. Hepa-totoxicity, usually in the form of reversible cholestatic jaundice, has been reported for either drug. Acute hepatic necrosis may also ensue with high-dose 6-MP therapy, whereas fatal veno-occlusive disease has been reported with 6-TG. Highdose therapy with 6-MP or 6-TG can cause tubular precipitation and crystalluria. 6-MP is used in ALL whereas 6-TG is active in AML.


Fludarabine is a 2-fluoromonophosphate derivative of adeno-sine arabinoside (ara-A) that is relatively water soluble and resistant to rapid deamination by adenosine deaminase (ADA). Upon dephosphorylation in plasma to 2-fluoro-ara-A, intracellular rephosphorylation by deoxycytidine kinase to its active form, 9-b-d-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP), is necessary for cytotoxicity. F-ara-ATP inhibits several important enzymes in DNA replication, including DNA polymerase and ribonucleotide reductase. Its incorporation into DNA leads to DNA chain termination, primarily at the 3'-end, in contrast to ara-C, which is incorporated into 5'-termini. It demonstrates synergism with ara-C and cisplatin.93,94

Fludarabine is cleared primarily by the kidneys. Although it has good oral bioavailability, an oral formulation is not yet available for commercial use. Myelosuppression is dose related and may be cumulative. Development of autoimmune hemolytic anemia may occur most commonly during the first three cycles of treatment. Fever occurs in approximately 25% of patients, although about one-third of these patients have a serious documented infection. Increased risk for opportunistic infections is in consequence to significant and protracted reduction in CD4+ T cells; hence, prophylaxis against Pneumocystis pneumonia is required. Pulmonary toxicity, manifested as fever, cough, and interstitial pneumonitis, has also been associated with this drug. Fludarabine is active not only against actively dividing cells but also in malignancies with low growth fraction such as chronic lymphocytic leukemia (CLL) and low-grade lymphomas.


Cladribine (2-CdA) is a deoxyadenosine analogue with a chloride attached to the 2-position of the adenine ring that renders it resistant to breakdown by ADA. Intracellular phosphoryla-tion by deoxycytidine kinase to the active 5'-triphosphate (2-CdATP) results in incorporation into DNA, leading to DNA chain termination and strand breaks; inhibition of DNA polymerases and ribonucleotide reductase ultimately results in inhibition of DNA synthesis. Cells with a high ratio of deoxycytidine kinase to deoxynucleotidase activity, such as lymphocytes, are particularly sensitive to the effects of cladribine. Similar to fludarabine, cladribine is cytotoxic to both actively dividing and nondividing cells. In resting cells, 2-CdATP seem to initiate the caspase cascade leading to apoptosis.95

Bioavailability of cladribine administered subcutaneously reaches nearly 100%. It can penetrate the blood-brain barrier, the CSF concentrations reaching about 25% of the plasma concentrations during continuous IV infusion. Cladribine is renally cleared and hence, should be used with caution in patients with renal insufficiency. Similar to fludarabine, it increases the intracellular concentrations of ara-CTP and probably other pyrimidine analogues as well. Immuno-suppression results from prolonged suppression of CD4+ T lymphocytes; thus, opportunistic infections, in addition to myelosuppression, are the major adverse complications with this drug. Cladribine is highly active in the treatment of hairy cell leukemia, Waldenstrom's macroglobulinemia, indolent lymphomas, and leukemias. Its activity in fludarabine-resistant cases however, is much diminished.


Pentostatin, or 2'-deoxycoformycin, is an adenosine analogue originally isolated from Streptomyces antibioticus but is now synthetically derived. It is a potent inhibitor of ADA, leading to high levels of deoxyadenosine and its triphosphate, which in turn inhibit ribonucleotide reductase in a negative feedback loop. Cells with high levels of deoxynucleoside kinase activity over 5-nucleotidase activity, such as lymphocytes, are most susceptible to the effects of ADA inhibition.96 Postulated mechanisms of cytotoxicity are similar to the other adenosine analogues. In addition, it also prevents methylation reactions mediated by S-adenosylhomocyteine hydrolase.

Renal elimination accounts for most of the clearance of pentostatin (more than 90%). Pentostatin is per se a nephro-toxic agent, and renal failure is dose limiting. Opportunistic infections arising from immunosuppression may occur. Nausea and vomiting are the most common nonhematologic toxicities. It is highly active in hairy cell leukemia, Walden-strom's macroglobulinemia, indolent lymphomas, and leukemias.

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