Cancer folic acid deficiency

In view of the reported growing importance ascribed to folic acid deficiency in the prevention of various disease conditions, such as neural tube defects, megaloblastic anemia, colon cancer, and colorectal cancer, a dissolution requirement is specified for folic acid when it is present in multivitamin-mineral combination products. Currently, the dissolution standard required in the official articles of dietary supplements (including vitamin-mineral combination products) places folic acid outside the index vitamin hierarchy. Therefore, a mandatory dissolution test for folic acid is required that is independent of and in addition to the mandatory index vitamin test for multivitamin preparations containing folic acid. 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

Duthie SI (1999) Folic acid deficiency and cancer mechanisms of DNA instability. British Medical Bulletin 55, 578-92. 

C. Pharmacodynamics Folic acid is converted to tetrahydrofolate by the action of dihydrofolate reductase (Figure 33-2, reaction 3). One important set of reactions involving tetrahydrofolate and dihydrofolate constitutes the dTMP cycle (Figure 33-2, reaction 2), which supplies the dTMP required for DNA synthesis. Rapidly dividing cells, in which DNA must be rapidly synthesized, are highly sensitive to folic acid deficiency. For this reason, antifolate drugs are useful in the treatment of various infections and cancers. 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

A decrease in erythrocyte production can be multifactorial. A deficiency in nutrients (such as iron, vitamin B12, and folic acid) is a common cause that often is easily treatable. In addition, patients with cancer and CKD are at risk for developing a hypoproductive anemia. Furthermore, patients with chronic immune-related diseases (such as rheumatoid arthritis and systemic lupus erythematosus) can develop anemia as a complication of their disease. Anemia related to these chronic inflammatory conditions is typically termed anemia of chronic disease. 

Moreover, unfavourable changes in intestinal bacteria can rednce their ability to inactivate carcinogens and, together with deficiencies of folic acid or methionine, predispose to colorectal cancer. 

Folic acid is used for the treatment of folate deficiency. Oral folic acid is usually the therapy of choice. For megaloblastic anemia doses of 5 mg daily for 4 months should be effective. Folinic acid is available in a parenteral formulation which may be indicated when oral therapy is not feasible and for rescue treatments following certain anti-cancer regimens. 

Folic acid antagonist overdose PO 2-15 mg/day for 3 days or 5 mg every 3 days. Megaloblastic anemia secondary to folate deficiency IM 1 mg/day Colon cancer IV 200 mg/m followed by 370 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals or 20 mg/m followed by 425 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals. 

Because the potential benefits outweigh the possibilities of harm, many experts recommend a daily multivitamin that does not exceed the RDA of it component vitamins. Multivitamins ensure an adequate intake for those vitamins—folic acid, vitamin B6, vitamin B12, and vitamin D—that are most likely to be deficient. However, the the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, or E multivitamins with folic acid or antioxidant combinations for the pre vention of cancer or cardiovascular disease. Most experts recommend against the use of p-carotene supplements, either alone or in combina Don, for the prevention of cancer or cardiovascular disease. 

Some of the unusual features of folic acid noled by investigators include (I) folic acid antagonists used in cancer therapy with temporary remissions (2) lolic acid occurs in chromosomes (3) folic acid is distributed throughout cells (4) needed for mitotic step metaphase to anaphase (5) antibody formation decreased in lolic acid deficiency (6) choline-sparing effects (7) analgesic in humans—pain threshold is increased (8) antisulfonatnide effects (9) enterohepatic circulation of folate (10) synthesized by psittacosis virus (11) concentrated in spinal fluid. 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fj,g per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others. 

Imprecisely diagnosed megaloblastic anaemia is the principal contraindication. Tumour cell proliferation in some cancers may be folate dependent and folic acid should be used in malignant disease only where there is confirmed folate deficiency anaemia. 

Folate is important for cells and tissues that divide rapidly therefore, high-dose methothrexate is often used to treat cancer because this compound interferes with folate metabolism. Methothrexate, however, has undesirable side effects, including inflammation in the digestive tract. It is not known whether folic acid supplementation can help control these side effects without decreasing the effectiveness of methro-threxate. Low-dose methothrexate is used to treat a variety of diseases, such as rheumatoid arthritis, lupus, psoriasis, asthma, and inflammatory bowel disease. Low-dose treatment can deplete folate stores and cause side effects similar to folate deficiency. In this case, supplemental folic acid may help reduce the undesirable effects of low-dose methothrexate without decreasing treatment effectiveness. 

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