Saijo N, Nishio K, Kubota N, Kanzawa F, Shinkai T, Karato A, Sasaki Y, Eguchi K, Tamura T, Ohe Y
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Chemother Pharmacol. 1994;34 Suppl:S112-7. doi: 10.1007/BF00684874.
The camptothecin derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin (CPT-11) has attracted the attention of clinicians because of its high antitumor activity against refractory solid cancers. We established two CPT-11-resistant cell lines, a non-small-cell lung-cancer cell line (PC-7/CPT-11) from the parental PC-7 line and an ovarian cancer cell line (HAC-2/CPT-11) from the parental HAC-2 line. The mechanisms of resistance to CPT-11 in PC-7/CPT-11 cells were reduced conversion of CPT-11 to its active metabolite SN-38 and point mutation topoisomerase I. Those in HAC-2/CPT-11 cells were reduction of topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase I inhibitors. No point mutation of the topoisomerase was observed in HAC-2/CPT-11 cells. We conducted two phase I trials using CPT-11 in combination with other anticancer agents. One was a phase I trial of CPT-11 and cisplatin given with a fixed dose of vindesine to patients with advanced non-small-cell lung-cancer and the other was a phase I study on a topoisomerase-targeting combination of CPT-11 and etoposide (VP-16) in patients with various malignant solid tumors. The results of the first trial indicated that the recommended dose of CPT-11 for phase II studies was 80 mg/m2 combined with 3 mg/m2 vindesine on days 1 and 8 and 60 mg/m2 cisplatin on day 1. In the second trial, the recommended dose of CPT-11/VP-16 given with recombinant granulocyte colony-stimulating factor (on days 4-17) was found to be 60/60 mg/m2. In both trials, diarrhea and granulocytopenia were considered to be dose-limiting toxicities.
喜树碱衍生物7-乙基-10-[4-(1-哌啶基)-1-哌啶基]-羰基氧基喜树碱（CPT-11）因其对难治性实体癌具有高抗肿瘤活性而引起临床医生的关注。我们建立了两种CPT-11耐药细胞系，一种是来自亲代PC-7系的非小细胞肺癌细胞系（PC-7/CPT-11），另一种是来自亲代HAC-2系的卵巢癌细胞系（HAC-2/CPT-11）。PC-7/CPT-11细胞对CPT-11的耐药机制是CPT-11向其活性代谢产物SN-38的转化减少以及拓扑异构酶I的点突变。HAC-2/CPT-11细胞的耐药机制是拓扑异构酶I活性降低以及拓扑异构酶对拓扑异构酶I抑制剂的敏感性降低。在HAC-2/CPT-11细胞中未观察到拓扑异构酶的点突变。我们进行了两项使用CPT-11联合其他抗癌药物的I期试验。一项是CPT-11和顺铂联合固定剂量长春地辛用于晚期非小细胞肺癌患者的I期试验，另一项是CPT-11和依托泊苷（VP-16）的拓扑异构酶靶向联合用于各种恶性实体瘤患者的I期研究。第一项试验的结果表明，II期研究中CPT-11的推荐剂量为80mg/m²，第1天和第8天联合3mg/m²长春地辛，第1天联合60mg/m²顺铂。在第二项试验中，发现联合重组粒细胞集落刺激因子（第4 - 17天）时CPT-11/VP-16的推荐剂量为60/60mg/m²。在两项试验中，腹泻和粒细胞减少均被认为是剂量限制性毒性。
