6-Mercaptopurine (6-MP) was the first of the thiopurine analogs found to have clinical efficacy in cancer therapy. This agent is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent (see Chapter 55). As with other thiopurines, 6-MP is inactive in its parent form and must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form the monophosphate nucleotide 6-thioinosinic acid, which in turn, inhibits several enzymes of de novo purine nucleotide synthesis (Figure 54–6). The monophosphate form is eventually metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. Significant levels of thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) also are formed from 6-MP. These metabolites may contribute to its cytotoxic action.
6-Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.
6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important difference because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50–75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol.
The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. Patients who have a pharmacogenetic syndrome involving partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities in the form of myelosuppression and gastrointestinal toxicity with mucositis and diarrhea.