7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials.
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.
Saijo
N
N
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishio
K
K
Kubota
N
N
Kanzawa
F
F
Shinkai
T
T
Karato
A
A
Sasaki
Y
Y
Eguchi
K
K
Tamura
T
T
Ohe
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D016466:CHO Cells; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D006224:Cricetinae; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms; D017354:Point Mutation; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin