Thiopurine Smethyltransferase

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and can be cured in most cases via chemotherapy. ALL is treated by a combination of various drugs; however, 6-mercaptopu-rine (6-MP) is one of the drugs required to maintain remission. It is mandatory to adjust 6-MP dosage according to the toxicity of 6-MP, which is mainly caused by the accumulation of the active metabolite 6-thioguanine triphosphate (6-TGTP) via the metabolite 6-thioinosine-monophosphate (6-TIMP; metabolic pathway shown in Fig. 2). 6-MP is an antimetabolite, which has to be activated to its triphosphate in order to be incorporated into DNA. On the other hand, 6-MP, but also 6-TIMP, can be inactivated by the enzyme TPMT to their inactive methylated metabolites 6-methylmecaptopurine (6-MMP) or 6-methylthioinosinemonophosphate (6-MTIMP). Thus decreased TPMT activity may lead to accumulation of the active 6-MP metabolite, and increased activity may lead to ineffective drug concentrations. Another drug which is methylated by TPMT is 6-thioguanine (6-TG), and indirectly the compound azathioprine, which is a prodrug of 6-MP. 6-TG is also being used as cytotoxic agent, and azathioprine is used as an immunosuppressant to treat rheumatic diseases. In all cases, elevated or depressed TPMT activity can cause ineffective accumulation of drug metabolites or toxic side effects, respectively. This can even include fatal myelosuppression after a standard dose of a thiopurine drug. Various other cases of TPMT-deficient patients showing severe side effects after 6-MP treatment are known. Therefore, the determination of polymorphisms of the TPMT gene prior to therapy might help to identify patients at risk of developing toxic side effects from 6-MP therapy. Genetic diversity (e.g., 238G>C, 460G>A, 719A>G) causes enhanced proteolysis of TPMT proteins and correlates

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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