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Effect of Hyperthermia on cis-Diamminedichloroplatinum(II) (Rhodamine 123)₂[tetrachloroplatinum(II)] in a Human Squamous Cell Carcinoma Line and a cis-Diamminedichloroplatinum(II)-resistant Subline¹

Dana-Farber Cancer Institute [T. S. H., B. A. T., K. N. S. C., M. E. K., J. B. L., M-H. L.] and Joint Center for Radiation Therapy [T. S. H.], Boston, Massachusetts 02115

The effect of concomitant hyperthermia on the cytotoxicities of cis-diamminedichloroplatinum(II) (CDDP), a newly synthesized drug, Pt(Rh-123)₂, and its chemical components, K₂PtCl₄ and rhodamine 123, was examined in vitro in a squamous cell tumor line of human origin (SCC-25) and in a CDDP-resistant subline (SCC-25/CP). No difference in the cytotoxicity of hyperthermia alone was observed between these cell lines. The dose-dependent cytotoxicities of 1-h exposures to CDDP and Pt(Rh-123)₂ were markedly increased at 42°C and 43°C in comparison to 37°C, and this effect was of the same magnitude in both cell lines (enhancements of approximately 1.5 logs at 42°C and 2.5 logs at 43°C for CDDP and 1.5 logs at 42°C and >3 logs at 43°C for Pt(Rh-123)₂). The use of hyperthermia with CDDP, however, did not lower survivals in the SCC-25/CP cells even to the levels seen in the parent line at 37°C. The cytotoxicities of K₂PtCl₄ and rhodamine 123 were essentially the same in the CDDP-sensitive and -resistant cells at all temperatures tested. The magnitude of the temperature effect was significantly greater for Pt(Rh-123)₂ than for its chemical components. No significant effect on CDDP or Pt(Rh-123)₂ accumulation was observed at 42, 43, 44 or 45°C in either cell line. DNA lesions, measured by alkaline elution, were significantly enhanced for CDDP in the SCC-25 cells at 42°C. These results suggest that treatment with hyperthermia and either CDDP or Pt(Rh-123)₂ should result in supraadditive anti-tumor effects, although the efficacy of CDDP plus hyperthermia will be significantly less once resistance to CDDP has developed. Since resistance to CDDP does not imply cross-resistance to Pt(Rh-123)₂, and since the effect of hyperthermia is somewhat greater for Pt(Rh-123)₂ than for CDDP at 43°C, Pt(Rh-123)₂ may be more selectively toxic to tumor cells when used with local hyperthermia versus normal cells outside the treated area, especially if resistance to CDDP has already developed.

¹ This work was supported by National Cancer Institute Grant R01-36508 (B. A. T.) and grants from the Deaconness Hospital and the Fuller Fund (T. S. H.).

² To whom requests for reprints should be addressed.

Received 12/10/87. Revised 4/19/88. Revised 5/27/88. Accepted 6/17/88.

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