Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity.
Uracil phosphoribosyltransferase (UPRT) of Escherichia coli origin can convert 5-fluorouracil (5-FU), a chemotherapeutic agent widely used for solid tumors, to an active intermediate, 5-fluorouridine-5'-monophosphate, as mammalian orotate phosphoribosyltransferase does. To examine whether the E. coli UPRT gene expressed in tumor cells can confer increased sensitivity to 5-FU, we retrovirally transduced Colon 26 cells, a murine colon carcinoma cell line, with the UPRT gene (Colon 26/UPRT cells) and tested the in vivo antitumoral effect of 5-FU in syngeneic immunocompetent mice. After 5-FU administration, tumors of Colon 26/UPRT cells regressed, whereas those of wild-type cells were unaffected. The mice that once eliminated Colon 26/UPRT tumors after 5-FU treatment rejected wild-type cells that were subsequently inoculated but not irrelevant syngeneic tumor cells. This suicide gene/prodrug system was less efficient in nude mice, suggesting that mature alphabeta T cells play a role in the antitumoral effect. The cytotoxicity mediated by the bystander effect was marginal in this system, contrary to the herpes simplex virus-thymidine kinase gene/ganciclovir system. Therefore, expression of the UPRT gene in tumor cells followed by 5-FU administration is a possible strategy for cancer gene therapy, but potentiation of the bystander effect is required for its therapeutic application.
Kawamura
K
K
Division of Pathology, Chiba Cancer Center Research Institute, Japan.
Tasaki
K
K
Hamada
H
H
Takenaga
K
K
Sakiyama
S
S
Tagawa
M
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D005472:Fluorouracil / Q000627:therapeutic use* / Q000633:toxicity; D008223:Lymphoma; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D005472:Fluorouracil