Cordel S, Heymann M F, Boisteau O, Oliver L, Le Pendu J, Grégoire M, Meflah K
INSERM U419, Institut de Biologie, Nantes, France.
Int J Cancer. 1997 Dec 10;73(6):924-8. doi: 10.1002/(sici)1097-0215(19971210)73:6<924::aid-ijc27>3.0.co;2-2.
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.
晚期结直肠癌通常对5-氟尿嘧啶（5-FU）化疗耐药。这与耐药细胞群体的出现有关，可能是由于选择过程导致的。因此，鉴定分子标志物和改进替代疗法仍然很重要。我们使用一种大鼠结肠癌细胞系（PROb）作为实验模型，该细胞系表现出与人类情况相似的特征。用5-FU治疗携带PROb肿瘤的大鼠可提高其生存率，但不能治愈。通过体外连续暴露于5-FU获得了一个PROb 5-FU耐药亚系（PRObR1）。与亲代PROb细胞相比，对5-FU的耐药伴随着胸苷酸合成酶活性增加2倍，并且在存在5-FU的情况下胸苷掺入量显著更高。出乎意料的是，在同基因大鼠中，与亲代PROb肿瘤相比，PRObR1肿瘤生长延迟。这归因于PRObR1细胞对宿主免疫反应的敏感性增加，因为在免疫受损的裸鼠中未观察到生长延迟，并且PROb和PRObR1细胞之间的增殖率没有可检测到的差异。5-FU治疗在延长携带PRObR1肿瘤大鼠的生存期方面无效。相比之下，一种将丁酸钠和重组白细胞介素-2（NaBut/rIL-2）联合的免疫治疗方案治愈了80%携带已建立PRObR1肿瘤的大鼠。我们的结果表明，NaBut/rIL-2治疗对5-FU化疗耐药的大鼠结肠癌有效。
