Schedule-dependent antitumor activity and toxicity of combinations of 5-fluorouracil and cisplatin/carboplatin against L1210 leukemia-bearing mice.
The combination of cisplatin (CDDP) and 5-fluorouracil (5-FU) has been reported to show marked therapeutic effects on experimental tumors and human malignancies, such as head and neck cancer. In these clinical studies, CDDP was administered on day 1 and followed by a 5-d continuous infusion of 5-FU. However, it was repeatedly shown that the sequence of 5-FU followed by CDDP is more active and less toxic in tumor-bearing animals. Thus, the optimal administration schedule of CDDP and 5-FU against L1210 murine leukemia was examined and compared with that of the combination of 5-FU and carboplatin (JM-8). The combinations of 5-FU (days 1 to 5) and CDDP, given either on day 1 or on day 5, showed a similar level of antitumor activity and toxicity. On the other hand, the combinations of 5-FU (days 1 to 5) and JM-8 given on day 5 showed significantly higher antitumor activity and rather less toxicity, as compared with the combinations on the reverse sequence. Thus, the treatment sequence of platinum compounds followed by a 5-d continuous infusion of 5-FU in many clinical studies appears to be extremely favorable to CDDP than JM-8. In addition, pathological examinations of died mice showed that accumulation of ascites and pleural effusion was inhibited most effectively by JM-8, given alone or in combination with 5-FU. These results strongly suggest that the combination of 5-FU followed by JM-8 will be expected to show more excellent antitumor activity against human malignancies, and may be especially useful in patients who are unable to tolerate CDDP-related toxicity.
Fujimoto
Shuichi
S
Division of Chemotherapy, Chiba Cancer Center Research Institute, Japan. sfujimot@chiba-cc.jp
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001201:Ascites / Q000139:chemically induced; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D013158:Splenic Diseases / Q000139:chemically induced; D015996:Survival Rate; D015431:Weight Loss / Q000187:drug effects
D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D005472:Fluorouracil