Chemotherapy purine metabolism

Pro-drug (a suicide substrate) converted by xanthine oxidase, forming alloxan-thine, which inhibits the enzyme — 4> purine metabolism —uric acid. Also used in cancer chemotherapy and radiation therapy. 

Senft, A. W. and Crabtree, G. W. (1983) Purine metabolism in the schistosomes potential targets for chemotherapy. Pharmacol. Ther. 20 341-356. 

Marr, J. J. (1991) Purine metabolism in parasitic protozoa and its relationship to chemotherapy. In Biochemical Protozoology (eds Coombs, G. and North, M.) Taylor and Francis, London pp. 524-536. 

It is of historical interest that Tetrahymena gelii, whose metabolism has been described in detail [387], is inhibited by 8-azaguanine [388] and other purine analogues [389, 390]. Of more importance to chemotherapy is the fact that pathogenic protozoa such as the trypanosomes respond in vitro to a number of... 

Correct answer = A. Methotrexate interferes with folate metabolism by acting as a competitive inhibitor of the enzyme dihydrofolate reductase. This starves cells for tetrahydrofolate, and makes them unable to synthesize purines and dTMP This is especially toxic to rapidly-growing cancer cells. Overproduction of dihydrofolate reductase, usually caused by amplification of its gene, can overcome the inhibition of the enzyme at the methotrexate concentrations used for chemotherapy, and can result in resistance of the tumor to treatment by this drug. 

The fifth chapter, Tetrahydrobiopterin and Related Biologically Important Pterins by Shizuaki Murata, Hiroshi Ichinose and Fumi Urano, describes a modern aspect of pteridine chemistry and biochemistry. Pteridine derivatives play a very important role in the biosynthesis of amino acids, nucleic acids, neurotransmitters and nitrogenmonooxides, and metabolism of purine and aromatic amino acids. Some pteridines are used in chemotherapy and for the diagnosis of various diseases. From these points of view, this article will attract considerable attention from medicinal and pharmaceutical chemists, and also heterocyclic chemists and biochemists. 

Mercaptopurine and thioguanine are both given orally (Table 55-3) and excreted mainly in the urine. However, 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation catalyzed by xanthine oxidase, whereas 6-TG requires deamination before it is metabolized by this enzyme. This factor is important because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used with chemotherapy in hematologic cancers to prevent hyperuricemia after tumor cell lysis. It does this by blocking purine oxidation, allowing excretion of cellular purines that are relatively more soluble than uric acid. Nephrotoxicity and acute gout produced by excessive uric acid are thereby prevented. Simultaneous therapy with allopurinol and 6-MP results in excessive toxicity unless the dose of mercaptopurine is reduced to 25% of the usual level. This effect does not occur with 6-TG, which can be used in full doses with allopurinol. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Shaw, T. and Locamini, S. A. (1995) Hepatic purine and pyrimidine metabolism implications for antiviral chemotherapy of viral hepatitis. Liver 15, 169-184. 

Antimetabolites compete with normal endogenous substrates and cause inhibition of the processes that require those substrates. Examples include purine and pyrimidine antagonists, which prevent nucleic acid replication and cellular division in cancer chemotherapy. Another example is methotrexate, which can inhibit folic acid metabolism. 

In this chapter we examine the synthesis and degradation of purines, pyrimidines, and hemes. These have complex structures, but are formed from simple precursors. All three can be synthesized in the body and have roles ranging from nucleic acids to hemoglobin. In addition to synthesis control of all three classes of compounds, a number of metabolic diseases associated particularly with purine and heme metabolism are discussed. The use of antimetabolites, as in chemotherapy, and the rationale for their use is presented. 

Since folic acid is critical to the formation of purines, antagonists of folic acid metabolism are used as chemotherapy drugs to inhibit nucleic acid synthesis and cell growth. Rapidly dividing cells, such as those found in cancer and tumors, are more susceptible to these antagonists. 

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