Expression of CYP2A6 in tumor cells augments cellular sensitivity to tegafur.
To examine the role of cytochrome P450 2A6 (CYP2A6) in the cellular sensitivity to an anti-tumor prodrug, tegafur (FT), a CYP2A6 cDNA construct was transfected into cells of a colon cancer cell line, DLD-1. CYP2A6-expressing cells (DLD-1 / CYP2A6 cells) more efficiently catalyzed the conversion of FT to 5-fluorouracil (5-FU) (2.6-fold) and the 7-hydroxylation of coumarin (7.9-fold) than cells transfected with a null construct (DLD-1 / null cells). These results indicated that the expressed CYP2A6 was functionally active. The extent of growth inhibition of the DLD-1 / CYP2A6 cells by FT was greater than that of DLD-1 / null cells; the difference between the DLD-1 / CYP2A6 and DLD-1 / null cells was statistically significant at the concentrations of 250, 500 and 1000 mM. 5-FU, an active metabolite of FT, inhibited the growth of both types of cells to the same extent. Thus, intracellular expression of CYP2A6 can sensitize cells to FT.
Murayama
N
N
Project Team for Pharmacogenetics, National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Sai
K
K
Nakajima
Y
Y
Kaniwa
N
N
Ozawa
S
S
Ohno
Y
Y
Sawada
J
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003374:Coumarins / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005472:Fluorouracil / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006900:Hydroxylation; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics*; D005641:Tegafur / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D003374:Coumarins; D005641:Tegafur; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D005472:Fluorouracil