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 subline

Abstract

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 degrees C and 43 degrees C in comparison to 37 degrees C, and this effect was of the same magnitude in both cell lines (enhancements of approximately 1.5 logs at 42 degrees C and 2.5 logs at 43 degrees C for CDDP and 1.5 logs at 42 degrees C and greater than 3 logs at 43 degrees 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 degrees 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 degrees C in either cell line. DNA lesions, measured by alkaline elution, were significantly enhanced for CDDP in the SCC-25 cells at 42 degrees 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 degrees 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.