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.

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