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cis-Diamminedichloroplatinum(II) Resistant Human Tumor Cell Lines Are Collaterally Sensitive to PtCl₄(Rh-123)₂: Evidence for Mitochondrial Involvement¹

Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Three human tumor cell lines made resistant to cis-diamminedichloroplatinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl₄(Rh-123)₂] than are the corresponding parental cell lines. The CDDP-resistant cells have higher intracellular concentrations of PtCl₄(Rh-123)₂ for the same exposure 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 greater 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 CDDP-resistant lines. Exposure of the cells to each of the mitochondrial effectors, chloramphenicol, FCCP, oligomycin, or antimycin prior to and during exposure to CDDP or PtCl₄(Rh-123)₂ had variable effects on the cytotoxicity of the platinum complexes in the parental lines. However, there was a consistent decrease in the cytotoxicity of PtCl₄(Rh-123)₂ in the CDDP-resistant cells in the presence of the mitochondrial effectors such that, in some cases, the CDDP-resistant lines were now less responsive to PtCl₄(Rh-123)₂ than were the parent cell lines. These studies indicate that mitochondrial alterations may be an important component of CDDP resistance in these cell lines and that PtCl₄(Rh-123)₂ may represent a prototype platinum complex useful in the treatment of CDDP resistant tumors.

¹ This work was supported by R01-CA47379 and R01-CA50174.

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Received 9/24/93. Accepted 1/17/94.