Cancer methylenetetrahydrofolate

MA J, STAMPFER M J, GIOVANNUCCI E, ARTIGAS C, HUNTER D J, FUCHS C, WILLETT W C, SELHUB J, HENNEKENS c H and ROZEN R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer . Cancer Res, 57, 1098-102. 

Cohen V, Panet-Raymond V, SabbaghianN et al. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003 9 1611-1615. 

Sohn KJ, Croxford R, Yates Z et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J... 

Aplenc R, Thompson J, Han P et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005 65 2482-2487. 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Unfortunately, the 5-fluorouracil used to make FdUMP can be incorporated into RNA by salvage routes normally used for uracil, thereby interfering with the function of messenger RNA in both cancer and normal cells. As a result, molecular modeling is currently being employed to design coenzymes that replace 5,10-methylenetetrahydrofolate and cause dUMP s transient covalent bond to become trapped during catalysis. 

Etienne M C, Formento J L, Chazal M, et al. (2004). Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Pharmacogen. 14 785-792. 

Etienne, M. C., lie, K., Formento, J. L., et al. (2004) Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms relationships with 5-fluorouracil sensitivity. Br. J. Cancer 90, 526-534. 

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