MODULATION OF [CIS-DIAMINEDICHLOROPLATINUM(II) HYPERTHERMIA] THERAPY BY INHIBITORS OF ARACHIDONIC-ACID METABOLISM

Abstract

Previous studies have shown that hyperthermia is an effective modulator of cis-diamminedichloroplatinum(II) (CDDP) cytotoxicity. We have examined the potential of inhibitors of the arachidonic acid metabolism to increase the antitumor activity of CDDP and hyperthermia. Sulindac and diflunisal are cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs (NSAIDS) and phenidone is a lipoxygenase inhibitor. Using the FSaIIC in vivo-in vitro excision assay, neither five daily injections of sulindac nor diflunisal added to the killing of FSaIIC cells achieved by one injection of CDDP at normal temperature. When the i.p. injection of CDDP and the NSAIDS were followed immediately by hyperthermia treatment to the tumor bearing limb at 43-degrees-C for 30 min, the cell killing achieved was increased by 2-3-fold by diflunisal over the dose range of CDDP examined but was unaffected by sulindac. Phenidone did not alter the cell killing achieved by CDDP at normal temperature or when the CDDP was followed by local hyperthermia, but use of a combination of sulindac or diflunisal plus phenidone increased the cell killing achieved by 2-10-fold when used with local hyperthermia over the dose range of CDDP tested. In tumor growth delay (TGD) studies, addition of five daily injections of sulindac, diflunisal or phenidone did not increase the TGD achieved by CDDP at normal temperature and neither diflunisal nor phenidone markedly increased the TGD produced by CDDP in conjunction with local hyperthermia, but the administration of sulindac resulted in about a 3-fold increase in TGD as did use of a combination of diflunisal or sulindac plus phenidone. These results indicate that inhibitors of arachidonic acid metabolism can increase the cell killing and the tumor growth delay produced by CDDP plus local hyperthermia.