We investigated the correlation between antitumor efficacy and kinetics of tumor and normal tissue apoptosis when cis-diamminedichloroplatinum (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 with 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 and normal tissue (thymus and ileum) over 96 h following the same treatments. 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 with 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 AUC of percentage thymus apoptosis for 1 h WBH + CDDP was 25% of that of 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 apoptosis than 2 h WBH + CDDP, a 1 h duration of WBH + CDDP may be a therapy that is both, as effective as, and safer than a 2 h duration of WBH + CDDP.

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