Potentiation of platinum analogue cytotoxicity by hyperthermia

Carboplatin and iproplatin, two new analogues of cisplatin, appear to have comparable activity in the treatment of advanced ovarian cancer, but minimal nephro- and neurotoxicities. Hyperthermia can potentiate the cytoxicity of cisplatin in vitro and in vivo, but systemic treatment with the combination has proven unsafe in patients. To provide the rationale for an alternative approach, we evaluated the relative degree of additivity between hyperthermia and the three platinum analogues in vitro against a human ovarian adenocarcinoma cell line, UACC-66. All drug and heat treatments were simultaneous for 1 h. Platinum analogue concentrations covered a five-log range from 0.001 to 100 micrograms/ml and hyperthermia temperatures included 38.5 degrees, 40 degrees, 41.5 degrees, and 43 degrees C. A tumor clonogenic assay was used to quantitate heat-drug interactive effects against the UACC-66 cells, and statistical analysis was performed using the median-effect equation of Chou. When combined with heat, the in vitro concentrations of the three platinum analogues were between 5% and 25% of those required at 37 degrees C to inhibit 50%-70% of the UACC-66 tumor colony-forming units. For each drug when combined with heat, a 3 degrees C incremental increase in temperature (i.e., from 37 degrees C to 40 degrees C or from 40 degrees C to 43 degrees C) was associated with a ten-fold decrease in ID50 drug concentration. We conclude that the synergistic effects of both carboplatin and iproplatin with hyperthermia at all temperatures above 37 degrees C provide a rationale for design of clinical trials in patients with ovarian cancer using these hyperthermia-drug combinations.