Purines antimetabolites

6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the purines hypoxanthine and guanine, which must be activated by nucleotide formation, according to the following scheme  

ThiolMP and ThioGMP are feedback inhibitors of phosphoribosylpyrophosphate amido-transferase, which is the first, and rate-limiting step in the synthesis of purine. In addition, these analogs inhibit the de novo biosynthesis of purine and block the conversion of inosinic acid to adenylic acid or guanylic acid. The triphosphate nucleotides are incorporated into DNA, and this results in delayed toxicity after several cell divisions. 

6-Mercaptopurine is used in the treatment of acute lymphoid leukemia. Maintenance therapy makes use of both methotrexate and 6-mercaptopurine. Mercaptopurine is absorbed well from the gastrointestinal tract. It is metabolized through (1) methylation of the sulfhydryl group and subsequent oxidation, and (2) conversion to 6-thiouric acid with the aid of xanthine oxidase, which is inhibited by allopurinol. Mercaptopurine may cause hyperuricemia. Its chief toxicities are hepatic damage and bone marrow depression. 

Thioguanine is used in patients with acute granulocytic leukemia, usually in combination with 

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The answer is b. (Hardmanr p 1241.) Busulfan is an alkylating agent that, in contrast to other alkylators, is an alkylsulfonate. Thioguanine is a purine antimetabolite. Bleomycin is classified as a chemotherapeutic... 

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. 

Folate antagonists Purine antimetabolites Pyrimidine antimetabolites... 

Purine Antimetabolites. Purine synthesis can be blocked by 6-mercaptopurine (7.77) and 6-thioguanine (7.78). Both require conversion to the mononucleotide in a lethal synthesis —a mechanism distinguished from the formation of suicide substrates in that the enzyme that transforms the inactive pro-dmg to the active inhibitor is different from the enzyme that is being blocked. inhibitors are formed and bound by the same... 

It is a purine antimetabolite which has marked effect on T-lymphocytes, suppresses cell mediated immunity (CMI). It selectively affects differentiation and functions of T cells and inhibits cytolytic lymphocytes. It is used primarily as immunosuppressant in organ transplantation, progressive rheumatoid arthritis and some other autoimmune diseases. 

Azathioprine and 6-mercaptopurine (6-MP) are purine antimetabolites that have immunosuppressive properties (see Chapters 54 and 55). 

Antimetabolites that are used to prevent the formation of DNA may be classified as antifolates, purine antimetabolites and pyrimidine antimetabolites (Table 7.5). Antifolates are believed to inhibit dihydrofolate reductase (DHFR). This enzyme is responsible for catalysing the conversion of dihydro-folic acid (DHF or FH2) to tetrahydrofolic acid (THF or FH4), which occurs in... 

Reversed-phase HPLC will find increased application in the analysis of purine antimetabolites and nucleoside antibiotics, both in the chemical laboratory for monitoring serum levels in chemotherapeutic treatment and in quality control in the pharmaceutical industry. In addition, RPLC will be used as a clinical diagnostic tool and aid the clinician in the detection of disease, in confirming a diagnosis, and in monitoring the causes of disease or effectiveness of therapy. 

Hande KR (2001) Purine antimetabolites. In Cancer Chemotherapy and biotherapy. Principles and practice (Chabner BA, Longo DL, eds), pp 295-314. Philadelphia Lipincott Williams and Wilkins. 

Mercaptopurine (CCS) Purine antimetabolite (S phase) bioactivated by HGPR transferase Acute lymphocytic leukemia immunosuppression (azathioprine forms 6-MP) BMS, hepatotoxicity (jaundice, necrosis), GI distress... 

Answer C. The purine antimetabolite 6-mercaptopurine is bioactivated in cancer cells by the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT). The most common form of resistance to 6-MP is a decrease in activity of this enzyme. Azathioprine, a drug used as an immunosuppressant, is closely related to 6-MP and also requires bioactivation to exert cytotoxic actions. 

Fludarabine is a purine antimetabolite. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidara-bine. Fludarabine s metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. It is indicated in refactory or progressive chronic B-ceU lymphocytic leukemia. 

Pentostatin is a purine antimetabolite. It is a potent transition-state inhibitor of the enzyme adenosine deaminase (ADA) that leads to cytotoxicity because of elevated intracellular levels of dATP that can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. It is indicated in the treatment for both untreated and alpha-interferon-refractory hairy-cell leukemia and as palliative therapy of chronic lymphocytic leukemia, prolympho-cytic leukemia and cutaneous T-cell lymphoma. 

Thioguanine, a purine antimetabolite (2 mg/kg daily p.o.), is indicated in the treatment of acute lymphoblastic and myelogenous leukemia, and chronic granulocytic leukemia. 

Decreased activation of prodrugs Resistance to the purine antimetabolites (mercapto-purine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouradl) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. 

Mechanisms of action and resistance Mercaptopurine and thioguanine are purine antimetabolites. Both drugs are activated by hypoxanthine-guanine phosphoribosyltrans-ferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine... 

Clinical use Purine antimetabolites are used mainly in the acute leukemias and chronic myelocytic leukemia. 

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