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.