Hyperthermic enhancement of cell killing by five platinum complexes in human malignant melanoma cells grown as monolayer cultures and multicellular spheroids.

Abstract

The cytotoxic properties of hyperthermia combined with cis-diammine-dichroloplatinum(II) (CDDP), and recently developed platinum complexes, (Glycolato-O-O')diammineplatinum(II) (254-S), cis-1-1-cyclobutane-dicarboxylate-(R)-2-methyl-1-4-butanediammine platinum(II) (NK-121), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA), and (-)-R-[2-(aminomethyl)pyrrolodine](1,1- cyclobutanedicarboxylato)-platinum(II)monohydrate (DWA-2114R) were studied in vitro in monolayer cultures and multicellular spheroids of HMV-I human malignant melanoma cells. Hyperthermia at 44 degrees C for 30 min was applied during the latter part of 1 hr drug exposure. Cell survival was compared after drug treatments in cells exposed or not exposed to heat. Cytotoxicity was assessed by clonogenic assays. In exponentially growing monolayer cultures, marked hyperthermic sensitization was observed by each of the five platinum complexes studied. The dose modifying factors obtained were almost the same in these drugs. Unlike monolayer cells, the spheroids were appreciably different with regard to hyperthermic sensitization among platinum complexes. The order of the magnitude was as follows: CDDP, DWA-2114R, 254-S, CBDCA, and NK-121. In the low dose region, however, 254-S was the most thermally sensitized. These results suggest that the microenvironment factor within spheroids may significantly affect the cytotoxicity of platinum complexes combined with hyperthermia. On the basis of these findings using spheroids, CDDP, DWA2114R, and 254-S appear to be promising platinum complexes for use with hyperthermia clinically as far as hyperthermic sensitization is concerned.