SEQUENCE DEPENDENCE OF THE HYPERTHERMIC POTENTIATION OF CARBOPLATIN-INDUCED CYTOTOXICITY AND INTRACELLULAR PLATINUM ACCUMULATION IN HELA-CELLS

We have examined the enhancement of cytotoxic effects of cis-diammine- 1,1-cyclobutane dicarboxylate platinum(II) (carboplatin) by hypertherm ia in HeLa cells using different regimes of timing, and sequence. The results were compared with those obtained with cis-diamminedichloropla tinum(II) (cisplatin). We found that cisplatin simultaneously combined with heat was the most cytotoxic toward HeLa cells of the various tim ing and sequencing conditions studied. On the other hand, for carbopla tin, drug treatment immediately following or during heat exposure show ed the greatest effect. Intracellular platinum concentration in HeLa c ells treated with heat before carboplatin showed a 2.75-fold incrase o ver that in cells treated with the drug alone. The ratios for carbopla tin given before, or during heating, were 0.67 and 1.42 respectively. Simultaneous exposure of cells to cisplatin, and heat led to a 1.64-fo ld enhancement in cisplatin accumulation, compared to 0.92- and 1.24-f old increase for cells treated with cisplatin before and after heat re spectively. Although each drug exposure prior to heat was-less cytotox ic toward HeLa cells than any other heat/drug combination sequences, t he platinum concentration was less than seen with each drug alone. Eve n though heat exposure prior to and during carboplatin showed a simila r toxicity, platinum concentration in cells treated with heat prior to carboplatin was higher than that in cells treated with heat and carbo platin simultaneously. Thus, increased cytotoxicity cannot always be e xplained on the basis of intracellular platinum concentration. it is c lear however that, differing from cisplatin, exposure of cells to heat prior to or during carboplatin administration results in the greatest cell kill.