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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

Antimetabolites: Purine Analogues

Thioguanine is an analogue of the natural purine gua-nine in which a hydroxyl group has been replaced by a sulfhydryl group in the 6-position.

Purine Analogues

Thioguanine (6-Thioguanine)


Thioguanine is an analogue of the natural purine gua-nine in which a hydroxyl group has been replaced by a sulfhydryl group in the 6-position. Two major mecha-nisms of cytotoxicity have been proposed for 6-thiogua-nine: (1) incorporation of the thio nucleotide analogue into DNA or RNA and (2) feedback inhibition of purine nucleotide synthesis. Both of these actions require initial activation of the drug by the enzyme hypoxanthine guanine–phosphoribosyltransferase (HGPRTase), as follows:

The product of this reaction, 6-TGMP, can eventu-ally be converted to deoxy-6-thioguanosine-triphos-phate (dTGTP), which has been shown to be incorpo-rated into DNA. Resistance of human leukemia cells to thioguanine has been correlated with decreased activity of HGPRTase and to increased inactivation of the thio nucleotides by alkaline phosphatase.


Thioguanine is slowly absorbed after oral adminis-tration; parent drug levels are barely detectable, and peak levels of metabolites occur only after 6 to 8 hours. Total urinary excretion of metabolites in the first 24 hours is 24 to 46% of the administered dose.


Thioguanine is used primarily as part of a combined induction of chemotherapy in acute myelogenous leukemia.


Myelosuppression, with leukopenia and thrombocy-topenia appearing 7 to 10 days after treatment, and mild nausea are the most common adverse effects. Liver toxi-city with jaundice has been reported in some patients but appears to be less common than with mercaptopurine.


Mercaptopurine (6-Mercaptopurine)


Mercaptopurine (Purinethol) is an analogue of hypo-xanthine and was one of the first agents shown to be ac-tive against acute leukemias. It is now used as part of maintenance therapy in acute lymphoblastic leukemia. Mercaptopurine must be activated to a nucleotide by the enzyme HGPRTase. This metabolite is capable of inhibiting the synthesis of the normal purines adenine and guanine at the initial aminotransferase step and in-hibiting the conversion of inosinic acid to the nu-cleotides adenylate and guanylate at several steps. Some mercaptopurine is also incorporated into DNA in the form of thioguanine. The relative significance of these mechanisms to the antitumor action of mercap-topurine is not clear.


Resistance to mercaptopurine may be a result of de-creased drug activation by HGPRTase or increased in-activation by alkaline phosphatase.

The plasma half-life of an intravenous bolus injec-tion of mercaptopurine is 21 minutes in children and 47 minutes in adults. After oral administration, peak plasma levels are attained within 2 hours. The drug is 20% bound to plasma proteins and does not enter the CSF. Xanthine oxidase is the primary enzyme involved in the metabolic inactivation of mercaptopurine.


Mercaptopurine is used in the maintenance therapy of acute lymphoblastic leukemia. It also displays activ-ity against acute and chronic myelogenous leukemias.


The major toxicities of mercaptopurine are myelo-suppression, nausea, vomiting, and hepatic toxicity.



Fludarabine (Fludara) is a fluorinated purine analogue of the antiviral agent vidarabine. The active metabolite, 2-fluoro-ara-adenosine triphosphate, inhibits various enzymes involved in DNA synthesis, including DNA polymerase- , ribonucleotide reductase, and DNA pri-mase. Unlike most antimetabolites, it is toxic to nonpro-liferating as well as dividing cells, primarily lymphocytes and lymphoid cancer cells.


The drug is highly active in the treatment of chronic lymphocytic leukemia, with approximately 40% of pa-tients achieving remissions after previous therapy with alkylating agents has failed. Activity is also seen in the low-grade lymphomas.


The major side effect is myelosuppression, which contributes to fevers and infections in as many as half of treated patients. Nausea and vomiting are mild. Occasional neurotoxicity has been noted at higher doses, with agitation, confusion, and visual disturbances.




Pentostatin (Nipent, deoxycoformycin) is a purine iso-lated from fermentation cultures of the microbe Streptomyces antibioticus. Its mechanism of action in-volves inhibition of the enzyme adenosine deaminase, which plays an important role in purine salvage path-ways and DNA synthesis. The resulting accumulation of deoxyadenosine triphosphate (dATP) is highly toxic to lymphocytes.


Pentostatin is effective in the therapy of hairy cell leukemia, producing remissions in 80 to 90% of patients and complete remissions in more than 50%. The major toxic effects of the drug include myelosuppression, nau-sea, and skin rashes.




Cladribine (Leustatin) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the enzyme deoxycytidine kinase. Like the other purine antimetabolites, it is relatively selective for both normal and malignant lymphoid cells and kills resting as well as dividing cells by mechanisms that are not completely understood.


The drug is highly active against hairy cell leukemia, producing complete remissions in more than 60% of pa-tients treated with a single 7-day course. Activity has also been noted in other low-grade lymphoid malignan-cies. The major side effect is myelosuppression.


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