5-FLUOROURACIL-RESISTANT COLONIC TUMORS ARE HIGHLY RESPONSIVE TO SODIUM-BUTYRATE INTERLEUKIN-2 BITHERAPY IN RATS

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 o f molecular markers and the improvement of alternative therapies thus remain important. We have used as an experimental model a rat colon ca ncer 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. Resist ance to 5-FU was accompanied by a 2-fold increase in thymidylate synth ase 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 compar ed with parental PROb tumors. This was ascribed to an increased sensit ivity of PRObR1 cells to host immune response since no growth delay wa s observed in immunocompromised nude mice and since there was no detec table difference in proliferation rates between PROb and PRObR1 cells. 5-FU treatment was inefficient in prolonging the survival of rats bea ring PRObR1 tumors. In contrast, an immunotherapeutic protocol combini ng sodium butyrate and recombinant interleukin-2 (NaBut/rIL-2) cured 8 0% of the rats bearing established PRObR1 tumors. Our results suggest that NaBut/rIL-2 treatment is efficient against 5-FU-chemoresistant ra t colon cancer. (C) 1997 Wiley-Liss, Inc.