No abstract

We have recently demonstrated that a treatment combining the cell differentiating agent sodium butyrate (NaBut) and interleukin-2 (IL2) resulted in a remission of established peritoneal colorectal carcinomatosis in rats. NaBut or IL2 treatment alone, never cured these tumour-bearing rats. In the present investigation, we report that NaBut-treatments induce apoptosis in the colonic cancer cells both in vitro and in vivo. We postulated that the significant therapeutic effect of NaBut/IL2 treatment can be mainly attributed to a NaBut-induced apoptosis of the tumoural cells increasing their immunogenicity. Indeed, treatment which combined apoptotic bodies (apobodies) as cell vaccine, plus IL2 immunotherapy significantly increased tumour remission and survival rate of the vaccinated rats, whereas IL2 treatment alone did not. We observed that the cured rats presented long-term protection against subsequent challenge with the parental tumour cells. This latter result suggests that these treatments generate an immune protection. This was confirmed by the presence, in the sera of the cured rats, of anti-tumoural antibodies directed against both the apobodies and the tumour cells, but not against normal colonocytes. In addition, we show that injections of apobodies before administration of the parental tumour cells results in a partial protection. We provide the first evidence that apobodies, derived from cancer cells after NaBut-treatment, induce a specific immune response against parental tumours cells. These data suggest that the distinctive immunologic properties of apobodies could provide a valuable tool in colorectal cancer immunotherapy.

This study validates the Capella classification as easy to apply and useful in predicting clinical outcome.

No abstract

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.