A research team has found that a specific mutation in a gene critical to folate metabolism alters the sensitivity of colon and breast cancer cells to common chemotherapy drugs, suggesting that the gene might be a useful marker for tailoring chemotherapy or that it is a potential target to improve sensitivity to chemotherapy.

Folate is a form of a B vitamin that is critical for DNA synthesis, DNA repair, and epigenetic regulation. About 35% of the general North American population has a common mutation in an enzyme, MTHFR, that is critical to the metabolism of folate. This mutation is associated with changes in cellular composition of folates.

Because the response of cancer cells to two common chemotherapy drugs, 5-fluorouracil (5FU) and methotrexate, is dependent on the interaction with folate metabolism, Kyoung-Jin Sohn and Young-In Kim, M.D., of the University of Toronto, tested whether this common mutation-called the MTHFR C677T polymorphism-affected the sensitivity of cancer cells to 5FU and methotrexate.

The authors found that colon and breast cancer cells that had the mutation had decreased MTHFR activity, altered intracellular folate distribution, accelerated cellular growth rate, and increased chemosensitivity to 5FU.

Breast cancer cells had decreased chemosensitivity to methotrexate. In mice, tumors with the mutated gene grew faster but were more sensitive to 5FU than tumors with the normal gene.

"Our data suggest that the MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy," the authors write. "Furthermore, our data suggest that antisense inhibition of MTHFR may be a potential target for increasing chemosensitivity of colon and breast cancer cells to 5FU-based chemotherapy."

SOURCE:
Journal of the National Cancer Institute, January 21, 2004