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Pharmacogenetics

Small change, large effect

Nature Reviews Cancer volume 4, page 175 (2004)Cite this article

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MTHFR catalyses the conversion of 5,10-methylene THF to 5-methyl THF. The 667T variant of MTHFR is less active, so 5,10-methylene THF accumulates. The authors tested whether the polymorphism altered the effectiveness of the antifolate drugs 5-fluorouracil (5-FU) and methotrexate (MTX) — which are used widely to treat breast and colon cancer — and correlated with their known mechanisms of action.

The authors took a colon cancer and a breast cancer cell line with endogenous 667C MTHFR and transfected them with 667T variant MTHFR. Enzyme activity was 35% lower in the 667T MTHFR cells and the intracellular distribution of folates had also changed: levels of 5-methyl THF were about 12% lower and 5,10-methylene THF levels were about 10% higher. These cells grew faster than 667C variant cells, probably because 5,10-methylene THF is required for DNA synthesis.

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References

ORIGINAL RESEARCH PAPER

  1. Sohn, K. -J. et al. Effect of the methylenetetrahydrofolate reductase C667T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J. Natl Cancer Inst. 96, 134–144 (2004)

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FURTHER READING

  1. Ulrich, C. M., Robien, K. & McLeod, H. L. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nature Rev. Cancer 3, 912–920 (2003)

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Authors
  1. Ezzie Hutchinson
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Hutchinson, E. Small change, large effect. Nat Rev Cancer 4, 175 (2004). https://doi.org/10.1038/nrc1309

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  • DOI: https://doi.org/10.1038/nrc1309

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