CIS-DIAMMINEDICHLOROPLATINUM(II) RESISTANT HUMAN TUMOR-CELL LINES ARECOLLATERALLY SENSITIVE TO PTCL4(RH-123)(2) - EVIDENCE FOR MITOCHONDRIAL INVOLVEMENT

Three human tumor cell lines made resistant to cis-diamminedichloropla tinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl4(Rh-123)(2)] than are t he corresponding parental cell lines. The CDDP-resistant cells have hi gher intracellular concentrations of PtCl4(Rh-123)(2) for the same exp osure than do the parent cells. Each of the CDDP-resistant cell lines has an increased level of cytochrome c oxidase activity compared with the parent cell lines, indicating that the resistant cells have greate r mitochondrial mass or activity than the parent cells. In fact, there was a linear correlation between the increase in cytochrome c oxidase activity and the increased sensitivity to PtCl4(Rh-123)(2) in the CDD P-resistant lines. Exposure of the cells to each of the mitochondrial effecters, chloramphenicol, FCCP, oligomycin, or antimycin prior to an d during exposure to CDDP or PtCl4-(Rh-123)(2) had variable effects on the cytotoxicity of the platinum complexes in the parental lines. How ever, there was a consistent decrease in the cytotoxicity of PtCl4(Rh- 123)(2) in the CDDP-resistant cells in the presence of the mitochondri al effecters such that, in some cases, the CDDP-resistant lines were n ow less responsive to PtCl4(Rh-123)(2) than were the parent cell lines . These studies indicate that mitochondrial alterations may be an impo rtant component of CDDP resistance in these cell lines and that PtCl4( Rh-123)(2) mag represent a prototype platinum complex useful in the tr eatment of CDDP resistant tumors.