Combination chemotherapy of human ovarian xenografts with intraperitoneal liposome-incorporated valinomycin and cis-diamminedichloroplatinum(II).
Intraperitoneal administration of liposomal valinomycin (MLV-VM) with cis-diamminedichloroplatinum(II) (cDDP) had significant antitumor activity against murine P388 leukemia and inhibited the growth of OVCAR-3 tumors in a nude mouse model of human ovarian cancer. This tumor is a teratoma originating in the ovary with pathogenesis and metastatic properties similar to those of human ovarian cancer. Drug was given to the mice once every 5 days for 4 doses beginning 1 day after i.p. implantation of 10(7) or 5 x 10(7) OVCAR-3 tumor cells. For P388 leukemia, drug was given i.p. once or on days 1 and 5 after tumor inoculation. Despite the use of low doses of MLV-VM, the antitumor activity of the combination [increase in life span (%T/C), 289%-294%] represents a 4-log cell kill over the additive effect of the two drugs, indicating a synergistic interaction between MLV-VM and cDDP. Likewise, low doses of the drug combination produced a synergistic interaction on human ovarian OVCAR-3 tumors, and tumor-free, long-term survivors were obtained. Combined therapy of liposome-incorporated valinomycin and cisplatin was well tolerated and produced no overlapping nephrotoxicity, although a decrease in liver enzyme markers (alkaline phosphatase and/or alkaline aminotransferase) with MLV-VM was observed. These results appear to suggest that MLV-VM with cDDP may have considerable potential for the treatment of ovarian cancer disseminated within the peritoneal cavity, although the frequency and sequence of drug administration may need to be improved.
Daoud
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Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman 99164-6510.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007941:Leukemia P388 / Q000188:drug therapy; D008081:Liposomes; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014634:Valinomycin / Q000008:administration & dosage
D004337:Drug Carriers; D008081:Liposomes; D014634:Valinomycin; D002945:Cisplatin