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thioguanine: profile and news
Other information Indication For treatment of acute nonlymphocytic leukaemia Pharmacology Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). Mechanism Of Action Thioguanine acts through its incorporation into DNA as a false purine base, and through an additional cytotoxic effect related to its incorporation into RNA. Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP). This nucleotide reaches high intracellular concentrations at therapeutic doses. TGMP interferes at several points with the synthesis of guanine nucleotides. It inhibits de novo purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. At one time, TGMP was thought to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have not shown this. Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of thioguanine. Thus, thioguanine has multiple metabolic effects and, at present, it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The net consequence of its action is a sequential blockade of the synthesis and utilization of the purine nucleotides. Drug Category Antimetabolites; Antineoplastic Agents; ATC:L01BB03 Brand Names/Synonyms BW 5071; CHEMBANK1056; Guanine, Thio-; Lanvis; NSC 752; TG; THIOGUANINE; Tabloid; Thg; Thioguanine; Tioguanin; Tioguanine; Wellcome U3b; X 27 Dosage Forms TABLETS Absorption Absorption of an oral dose of thioguanine in humans is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) Interactions -->Interactions for Thioguanine: There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. |
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