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7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials

  • Session 3: Clinical Trials and Applications
  • CPT-11, Topoisomerase I, Dose-limiting Toxicity, Resistance
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

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 of 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.

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Authors and Affiliations

  1. Pharmacology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, 104, Tokyo, Japan

    Nagahiro Saijo, Kazuto Nishio, Naohiro Kubota & Fumihiko Kanzawa

  2. Medical Oncology Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, 104, Tokyo, Japan

    Tetsu Shinkai, Atsuya Karato, Kenji Eguchi, Tomohide Tamura, Yuichiro Ohe, Fumihiro Oshita & Makoto Nishio

  3. Medical Oncology Division, National Cancer Center Hospital East, Kashiwanoha, Kashiwa City Chiba, Japan

    Yasutsuna Sasaki

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  1. Nagahiro Saijo
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  2. Kazuto Nishio
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  3. Naohiro Kubota
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  4. Fumihiko Kanzawa
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  7. Yasutsuna Sasaki
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Saijo, N., Nishio, K., Kubota, N. et al. 7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials. Cancer Chemother. Pharmacol. 34 (Suppl 1), S112–S117 (1994). https://doi.org/10.1007/BF00684874

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