6-Thioguanine toxicity

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with anthracyclines, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and lymphomas and has marginal activity against other tumors. Myelosuppres-sion is a major toxicity, as is severe bone marrow hypoplasia nausea and mucositis may also occur. 

Thioguanine is 5-30 times as toxic to rodents (depending on schedule) as 6-mercaptopurine and somewhat more effective against rodent neoplasms. 

Vora A, Mitchell CD, Lennard L et al. Medical Research Council. National Cancer Research Network Childhood Leukaemia Working Party. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia a randomised trial. Lancet 2006 368 1339-1348. 

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. 

THIOGUANINE An analogue of the purine base guanine, which is a normal component of DNA and RNA selection for resistance to the toxic effects of 6-thioguanine is the basis of several mutation-detection systems. 

Thiopurine methyltransferase Poor TPMT methylators 6-Mercaptopurine 6-Thioguanine Azathioprin Bone marow toxicity, hepatotoxicity... 

Bisschop D, Germain ML, Munzer M, Trenque T. Thioguanine, pancreatotoxicite [Thioguanine, pancreato-toxicity ] Therapie 2001 56(l) 67-9. 

Lilieyman JS. Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia a comparison of haematological toxicity and drug metabolite concentrations. Br J Haematol 1998 102(2) 439-43. 

Satti MB, Weinbren K, Gordon-Smith EC. 6-thioguanine as a cause of toxic veno-occlusive disease of the liver. I Clin Pathol I982 35(10) 1086-9I. 

Kao NL, Rosenblate HJ. 6-Thioguanine therapy for psoriasis causing toxic hepatic venoocclnsive disease. I Am Acad Dermatol 1993 28(6) 1017-18. 

Unlike 6-mercaptopurine and 6-thioguanine, 8-azaguanine difiused into Novikoff hepatoma cells (rat) without any sign of saturability, indicating that no carrier was involved. By varying the pH, it was shown that only the nonionized form entered the cell. 9-a-D-Arabinofuranosyl-8-azaadenine was found toxic to human epidermoid carcinoma cells in culture, whereas... 

Thioguanine is u.sed in treating acute leukemia, especially in comhination with cytarabine." - Cro.ss-resistance exists between thioguanine and mercaptopurine. The chief toxic effect is delayed bone marrow depre.ssion. resulting in leukopenia and eventually thrombocytopenia and bleeding. 

Antimetabolites Nephrotoxicity is generally not a major toxicity of antimetabolite therapy, except when these drugs are administered in high doses or in susceptible patients. Acute renal failure is the most common type of nephropathy induced by the antimetabolites with methotrexate treatment possessing the greatest risk. Acute renal failure has also been reported as a potential toxicity for 5-fluorouracil, 6-thioguanine, cytosine arabinoside, and 5-azacytidine. 

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