title: Antitumor activity of new combination chemotherapy with irinotecan hydrochloride and nedaplatin against human cervical cancer cell lines.
abstract: Antitumor activity of combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin was compared to that with CPT-11 and cisplatin. In vitro cytotoxicity of SN-38 (an active metabolite of CPT-11) in combination with nedaplatin or cisplatin was evaluated using three human cervical cancer cell lines (ME-180, CaSki and SiHa). IC50 values of nedaplatin against these three human cervical cancer cell lines were about 2-fold as high as those of cisplatin, indicating somewhat weak cytotoxic effects of nedaplatin. Interactions between two drugs in combination were investigated using a simultaneous-exposure schedule and analyzed by the IC50-based isobologram method. Simultaneous exposure to SN-38 with each platinum preparation showed synergistic and additive effects against ME-180 and SiHa. In vivo antitumor effects of CPT-11 in the combination with each platinum were studied using SiHa xenografts. While CPT-11, nedaplatin and cisplatin alone hardly showed any antitumor effects even at the maximum tolerated dose (MTD) levels, the combination chemotherapy with CPT-11 and nedaplatin or cisplatin resulted in significant antitumor effects even at three-quarter MTD of CPT-11 combined with two-third MTD of platinum. All treatments were tolerable for mice, indicating that the combinations did not cause significant enhancement in toxicity. In clinical application, nedaplatin causes a lower incidence of nephropathy and does not require the replacement of a large volume of fluid, which is needed for cisplatin administration, facilitating treatment at the out-patient clinic. In addition, the incidences of digestive disorder, peripheral neuropathy and auditory disorder are lower. These findings suggest that the combination chemotherapy with CPT-11 and nedaplatin for squamous cell cancer of uterine cervix is very useful in clinical practice. A dose-finding study should be conducted.
authors.affiliation: Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University School of Medicine, Sakai, Osaka 590-0132, Japan. yamamoto@sakai.med.kindai.ac.jp
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Michio
authors.initials: M
authors.lastname: Iwahana
authors.forename: Eiji
authors.initials: E
authors.lastname: Kumazawa
authors.forename: Koji
authors.initials: K
authors.lastname: Kakihata
authors.forename: Kunio
authors.initials: K
authors.lastname: Abe
authors.forename: Fuyumi
authors.initials: F
authors.lastname: Hirano
authors.forename: Akiko
authors.initials: A
authors.lastname: Tohgo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hoshiai
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Noda
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D009944:Organoplatinum Compounds; D000077146:Irinotecan; C053989:nedaplatin; D002945:Cisplatin; D002166:Camptothecin