EFFECT OF ALTERED DURATION OF 41.5-DEGREES-C WHOLE-BODY HYPERTHERMIA IN COMBINATION WITH CIS-DIAMMINEDICHLOROPLATINUM(II) ON TUMOR AND NORMAL TISSUE APOPTOSIS AND TUMOR RESPONSE IN RATS

We investigated the correlation between antitumor efficacy and kinetic s of tumor and normal tissue apoptosis when cis-diamminedichloroplatin um (II) (CDDP) was combined with two different durations of whole body hyperthermia [SH-WBH, at 41.5 degrees C for 1 h (1 h WBH) or 2 h (2 h WBH)]. Rats bearing a mammary adenocarcinoma (MTLn3) were treated wit h 1 or 2 h WBH +/- CDDP and then assessed for tumor growth delay (TGD) . A separate study examined the amount of induced apoptosis in tumor a nd normal tissue (thymus and ileum) over 96 h following the same treat ments. 1 h WBH + CDDP increased the TGD to 10.5+/-0.5 days, which was not statistically different from the TGD of 12.3+/-0.5 days obtained w ith 2 h WBH + CDDP. The area under the curve (AUC) of percentage tumor apoptosis for 1 h WBH + CDDP was 50% of that of 2 h WBH + CDDP. The A UC of percentage thymus apoptosis for 1 h WBH + CDDP was 25% of that o f 2 h WBH + CDDP, and the AUC of the score of ileal apoptosis for 1 h WBH + CDDP was 81% of that of 2 h WBH + CDDP. These data indicate that while 1 h WBH + CDDP induced less tumor apoptosis than 2 h WBH + CDDP , antitumor activity was enhanced to a similar degree by both 1 h and 2 h WBH + CDDP, and since 1 h WBH + CDDP caused less normal tissue apo ptosis than 2 h WBH + CDDP, a 1 h duration of WBH + CDDP may be a ther apy that is both, as effective as, and safer than a 2 h duration of WB H + CDDP.