title: Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.
abstract: Folic acid (FA) fortification and widespread supplemental use have significantly increased folate status in North America. Furthermore, >50% of colorectal cancer patients use FA supplement. The increased folate status may interfere with cancer chemotherapy. We investigated the effect of FA supplementation on chemosensitivity of human colon cancer cells to 5-fluorouracil (5-FU) using a xenograft model. Mice harboring human HCT116 colon cancer xenografts were randomized to receive the control, or 4× or 12.5× supplemental levels of FA. Within each diet group, mice were randomized to receive 5-FU+leucovorin or saline and xenograft growth and characteristics were determined. The expression of genes involved in folate metabolism and cancer treatment was determined. FA supplementation and 5-FU significantly interacted to influence xenograft growth (P < 0.007). At the control level, 5-FU significantly inhibited the growth of the xenografts (P < 0.0001). However, at the 4× supplemental level, 5-FU-treated xenografts grew faster than untreated xenografts (P = 0.048) while at the 12.5× supplemental level, 5-FU exhibited no effect. Cell proliferation, degree of necrosis, and expression of the selected genes did not significantly differ by the supplemental levels of FA. Our data suggest that FA supplementation may be detrimental to 5-FU chemotherapy of colon cancer and pose public health concern.
authors.affiliation: a Departments of Nutritional Sciences , University of Toronto , Toronto , Ontario , Canada.|f Keenan Research Centre for Biomedical Science of St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ishiguro
authors.affiliation: a Departments of Nutritional Sciences , University of Toronto , Toronto , Ontario , Canada.|f Keenan Research Centre for Biomedical Science of St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Yang
authors.affiliation: c Medicine, University of Toronto , Toronto , Ontario , Canada.|f Keenan Research Centre for Biomedical Science of St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Sohn
authors.affiliation: b Laboratory Medicine and Pathobiology, University of Toronto , Toronto , Ontario , Canada.|d Departments of Pathology , St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Streutker
authors.affiliation: b Laboratory Medicine and Pathobiology, University of Toronto , Toronto , Ontario , Canada.|d Departments of Pathology , St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Grin
authors.affiliation: g Statistical Consultant , Toronto , Ontario , Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Croxford
authors.affiliation: a Departments of Nutritional Sciences , University of Toronto , Toronto , Ontario , Canada.|c Medicine, University of Toronto , Toronto , Ontario , Canada.|e Medicine, St. Michael's Hospital , Toronto , Ontario , Canada.|f Keenan Research Centre for Biomedical Science of St. Michael's Hospital , Toronto , Ontario , Canada.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D005492:Folic Acid / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D005472:Fluorouracil; D005492:Folic Acid; D006710:Homocysteine; D027425:ATP-Binding Cassette, Sub-Family C Proteins