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5‐fluorouracil‐resistant colonic tumors are highly responsive to sodium butyrate/interleukin‐2 bitherapy in rats
Author(s) -
Cordel Sandrine,
Heymann MarieFrançoise,
Boisteau Olivier,
Oliver Lisa,
Le Pendu Jacques,
Grégoire Marc,
Meflah Khaled
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19971210)73:6<924::aid-ijc27>3.0.co;2-2
Subject(s) - sodium butyrate , fluorouracil , thymidylate synthase , butyrate , colorectal cancer , chemotherapy , cancer research , immune system , antimetabolite , thymidine , biology , medicine , cancer , cell culture , in vitro , pharmacology , immunology , biochemistry , genetics , fermentation
Advanced colorectal cancer is generally refractory to 5‐fluorouracil (5‐FU) chemotherapy. This is linked to the emergence of resistant cell populations, probably due to a selection process. The identification of molecular markers and the improvement of alternative therapies thus remain important. We have used as an experimental model a rat colon cancer cell line (PROb), which exhibits features similar to those of the human situation. 5‐FU treatment of rats bearing PROb tumors enhanced their survival but did not lead to cure. A PROb 5‐FU‐resistant subline (PRObR1) was obtained by continuous in vitro exposure to 5‐FU. Resistance to 5‐FU was accompanied by a 2‐fold increase in thymidylate synthase activity and a substantially higher incorporation of thymidine in the presence of 5‐FU, compared with parental PROb cells. Unexpectedly, in syngeneic rats, PRObR1 tumors exhibited delayed growth when compared with parental PROb tumors. This was ascribed to an increased sensitivity of PRObR1 cells to host immune response since no growth delay was observed in immunocompromised nude mice and since there was no detectable difference in proliferation rates between PROb and PRObR1 cells. 5‐FU treatment was inefficient in prolonging the survival of rats bearing PRObR1 tumors. In contrast, an immunotherapeutic protocol combining sodium butyrate and recombinant interleukin‐2 (NaBut/rIL‐2) cured 80% of the rats bearing established PRObR1 tumors. Our results suggest that NaBut/rIL‐2 treatment is efficient against 5‐FU‐chemoresistant rat colon cancer. Int. J. Cancer 73:924–928, 1997. © 1997 Wiley‐Liss, Inc.