Fujita F, Fujita M, Yamauchi T, Sakamoto Y, Shimozuma K, Inaba H, Taguchi T
Gan To Kagaku Ryoho. 1987 May;14(5 Pt 1):1297-304.
Despite the recent advances made in the development of anticancer drugs, any single chemotherapy treatment has only limited effects on cancers of the stomach, colon and breast, so that the combined use of multiple drugs is necessary for the treatment of solid tumors. In our previous studies with human gastrointestinal and breast cancers xenografted into nude mice, combination therapy with mitomycin C (MMC) and 5'-deoxy-5-fluorouridine (5'-DFUR) [I] or cisplatin (CDDP), vindesine (VDS) and 5'-DFUR [II] produced higher response rates than single-agent therapy with any one of these drugs. In the present study, the effectiveness of alternating chemotherapy with the combination regimens I and II was evaluated using 3 lines of cancer xenografts with special emphasis on relapse-free survival. Even in untreated controls, different influences of these cancers on the host as well as differences in their growth rates resulted in delayed tumor death in breast cancer (H-31) compared with pancreas (H-48) and colon (H-110) cancers. Four cycles of the regimen I drug combination failed to prolong life due to toxic side effects in every cancer line. In H-48 cancer, although regimen I alternated with regimen II achieved an inhibition rate (IR) of 96% with tumor shrinkage, 2 of 7 mice died of toxicity. In H-110 cancer, which is only sensitive to VDS, 4 cycles of regimen II alone produced an IR of 83.5%, which was slightly superior to alternating chemotherapy. In H-31 cancer, which retains considerable sensitivity to CDDP, MMC and 5'-DFUR, mice treated with alternating chemotherapy starting from regimen I for a total of 5 cycles attained a maximal IR of over 99% including disappearance of the tumor in 6 of 7 mice during the treatment course, and at the end of the experiment (20th week), all had survived with one in a relapse-free state, compared with the control group which had only 2 survivors. Thus, cyclic delivery of two non-cross-resistant drug combinations with optimal treatment doses and timing prevented toxic effects and induced long-term survival without relapse. Also, this appears to be the first study that has evaluated the effects of cancer chemotherapy in a human solid tumor-nude mouse system according to survival rate.
尽管抗癌药物的研发取得了最新进展，但任何单一的化疗治疗对胃癌、结肠癌和乳腺癌的疗效都很有限，因此治疗实体瘤需要联合使用多种药物。在我们之前将人胃肠道癌和乳腺癌异种移植到裸鼠体内的研究中，丝裂霉素C（MMC）与5'-脱氧-5-氟尿苷（5'-DFUR）[I]或顺铂（CDDP）、长春地辛（VDS）和5'-DFUR[II]联合治疗产生的缓解率高于这些药物中的任何一种单药治疗。在本研究中，使用3种癌症异种移植模型评估了交替使用联合方案I和II进行化疗的有效性，特别关注无复发生存率。即使在未治疗的对照组中，这些癌症对宿主的不同影响以及它们生长速度的差异，导致乳腺癌（H-31）的肿瘤死亡时间比胰腺癌（H-48）和结肠癌（H-110）延迟。方案I的药物联合使用4个周期未能延长每个癌症模型的生命，原因是出现了毒副作用。在H-48癌中，尽管方案I与方案II交替使用实现了96%的抑制率（IR），肿瘤缩小，但7只小鼠中有2只死于毒性。在仅对VDS敏感的H-110癌中，单独使用方案II进行4个周期治疗产生的抑制率为83.5%，略优于交替化疗。在对CDDP、MMC和5'-DFUR仍具有相当敏感性的H-31癌中，从方案I开始进行交替化疗共5个周期的小鼠，最大抑制率超过99%，包括在治疗过程中7只小鼠中有6只肿瘤消失，在实验结束时（第20周），与仅2只存活的对照组相比，所有小鼠均存活，其中1只处于无复发状态。因此，以最佳治疗剂量和时间循环给予两种非交叉耐药的药物联合方案可预防毒副作用，并诱导长期无复发生存。此外，这似乎是第一项根据生存率评估癌症化疗在人实体瘤-裸鼠系统中疗效的研究。
