Cancer folates

Colorectal cancer Folate/folic acid Methylation RCTs with folic acid did not show reduced risk of recurrence Figueiredo et al. (2011)... 

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting direcdy with nitrites, and consequently may potentially reduce cancer risk. 

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

Inhibitors of Folate Metabolism Provide Cancer Chemotherapy Antibacterial Antimalarial Drugs... 

GIOVANNUCCI E, STAMPFER M J, COLDITZ G A, HUNTER J, FUCHS C, ROSNER B A, SPEIZER F E and WILLETT w c (1998) Multivitamin use, folate, and colon cancer in women in the Nurses Health Study , Ann Intern Med, 129, 517-24. 

POGRIBNY J P, BASNAKIAN A G, MILLER B J, LOPATINA N G, POIRIER L A and JAMES S J (1995) Breaks in genomic DNA and within the P5 3 gene are associated with hypomethy lation in livers of folate/methyl-deficient rats . Cancer Res, 55, 1894-901. 

Zeegers, M.P. et al.. Are retinol, vitamin C, vitamin E, folate and carotenoids intake associated with bladder cancer risk Results from the Netherlands Cohort Study, Br. J. Cancer, 85, 977, 2001. 

The risk of colon cancer appears to be inversely related to calcium and folate intake. Calciums protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine, whereas dietary folate helps in maintaining normal bowel mucosa. Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and 3-carotene however, the benefit of dietary supplementation does not appear to be substantial.11... 

Folic acid and its metabolites called folates are essential to the cell s functions. They act as coenzymes in many biochemical processes. Folate-dependent enzymes are vital to rapidly dividing cell populations, such as the neoplastic or normal-stem cells. Therefore, they are a target for anti-folates in anti-cancer treatment. 

One of the greatest problems in treatment with MTX and other anti-folates is the fact that the cancer cells develop immunity to the drugs. It has been found34 that this immunity is due mainly to DHFR mutations where some amino-acid residues are replaced by others which do not bind to anti-folates. The desire to better understand the mechanism of binding of anti-folates to DHFR, in order that this problem will be remediated, has led to numerous experimental studies. In addition, theoretical studies have complemented the attempts to elucidate the mechanism. 

Roy, K., et al. Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter. Cancer Genet. Cytogenet. 1998, 305, 29-38. 

Drug efficacy is directly related to its intracellular concentration level, so it is necessary to evaluate the MTX concentration in cells. In particular, MTX is a folate antagonist, thus it binds to dihydrofolate reductase in competition with folate [71-77]. A low intracellular level of MTX caused by high efflux and low uptake in resistant cells is also the main disadvantage of MTX medication [78,79]. This leads to a high dosage of MTX for cancer treatment, which is also directly associated with adverse effects. 

Ross, J.F., Chaudhuri, P.K., and Ratnam, M. (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and established cell lines. Physiologic and clinical implications. Cancer 73, 2432-2443. 

The answer is c. (Katzung, pp 608-609, 932-9.13.) Methotrexate is classified as an anti metabolite with therapeutic uses in cancer chemotherapy and as an immunosuppressive agent indicated in the treatment of severe active classical rheumatoid arthritis. Leucovorin is related to methotrexate in that it is an antagonist of its actions. It can supply a source of reduced folate for the methylation reactions that are prevented by methotrexate. 

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