Role for alpha1,2-fucosyltransferase and histo-blood group antigen H type 2 in resistance of rat colon carcinoma cells to 5-fluorouracil.
5-Fluorouracil (5-FU) is a drug of standard use in chemotherapy of colon carcinoma. However, its efficacy is limited by inherent and acquired cell resistance. Major changes in histo-blood group antigenic expression, at times associated with poor prognosis, occur on colon cancer cells. To assess whether these antigens might play a role in the resistance to 5-FU, a rat model of colon carcinoma was used. We observed that in vivo treatment of tumors with the drug increased expression of antigen H type 2. The increase was also observed after in vitro short-term exposure to 5-FU, as well as on a cell-resistant variant selected by continuous exposure to the drug, and was accompanied by an increase in alpha1,2-fucosyltransferase activity, the key enzyme involved in synthesis of H antigens. Transfection of cells devoid of this enzymatic activity by an alpha1, 2-fucosyltransferase cDNA allowed expression of H type 2 antigen and increased resistance to 5-FU. Inversely, transfection of cells which possess enzymatic activity by a cDNA in anti-sense orientation reduced both H type 2 cell-surface antigen and resistance to the drug. These results demonstrate that, in this experimental model, alpha1,2-fucosyltransferase and H type 2 antigen are involved in cellular resistance to 5-FU.
Cordel
S
S
INSERM U419, Institute of Biology, Nantes, France.
Goupille
C
C
Hallouin
F
F
Meflah
K
K
Le Pendu
J
J
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006183:H-2 Antigens / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D014162:Transfection; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D005647:Fucosyltransferases; D006183:H-2 Antigens; D000097631:Galactoside 2-alpha-L-fucosyltransferase