Strategies for Increasing the Efficacy of and Overcoming Resistance to Platinum Complexes In Vivo
Current anticancer drugs often cause solid tumor masses to regress but cure is usually not possible. In order to improve efficacy, we have tested a number of modulators of platinum complexes in an effort to use the altered physiology of tumor masses to advantage. Using the FSaIIC murine fibrosarcoma, tumor cell excision survival versus bone marrow CFUC survival rations were obtained for CDDP (10 mg/kg), carboplatin (100 mg/kg) and D,L-Tetraplatin (20 mg/kg) i.p. used in conjunction with Fluosol-DA/carbogen breathing for 6 hr., Etanidazole, Lonidamine, Pentoxifylline, Etoposide, SR-4233 or hyperthermia. Large improvements in the tumor cell kill to bone marrow CFU-GM kill ratios of 21–276 times were obtained with Fluosol-DA/carbogen and CDDP or Carboplatin, with etanidazole and CDDP or carboplatin and with local hyperthermia and CDDP. Lesser improvements were evident with the other combinations. By using the Hoechst 33342 dye assay we were able to improve the ratio of dim (putative hypoxic) versus bright (putative oxic) cell killing produced by CDDP with Fluosol-DA/carbogen, etanidazole, etoposide and SR-4233. Hyperthermia and radiation when added to CDDP resulted in relatively increased killing of bright cells. In the tumor growth delay assay additive or greater effects with CDDP were produced by Fluosol-DA/carbogen, etanidazole, lonidamine, SR-4233, hyperthermia and x-ray., while pentoxifylline, acetazolamide and etoposide probably produced less than additive increase in tumor growth delay with CDDP. These results indicate that by using modulators, platinum complex drugs can be made to be more selectively toxic toward tumor cells in general and physiologically selected tumor cell subpopulations in particular. This sort of approach may improve the clinical management of solid tumors.
KeywordsPlatinum Complex Tumor Growth Delay Therapeutic Ratio Local Hyperthermia Hypoxic Tumor Cell
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