THERAPEUTIC EFFICACY AND APOPTOSIS AND NECROSIS KINETICS OF DOXORUBICIN COMPARED WITH CISPLATIN, COMBINED WITH WHOLE, BODY HYPERTHERMIA IN A RAT MAMMARY ADENOCARCINOMA

We have compared the therapeutic efficacy as well as the kinetics of t reatment-induced apoptosis and necrosis of the maximum tolerated dose (MTD) of doxorubicin (DOX) or cisplatin (CDDP) combined with long-dura tion, low-temperature whole-body hyperthermia (LL-WBH, at 40.0 degrees C for 6 hr), with the combination of the MTDs of either DOX or CDDP w ith short-duration, high-temperature WBH (SH-WBH, at 41.5 degrees C fo r 2 hr), in a rat mammary adenocarcinoma (MTLn3), The MTD of LL-WBH DOX resulted in increased therapeutic efficacy, compared with the MTD of DOX alone and SH-WBH + DOX, The MTD of LL-WBH + CDDP, however, did not increase therapeutic efficacy, when compared with the MTD of CDDP alone or SH-WBH + CDDP, The MTD of LL-WBH + DOX caused a significant d elay in the development of spontaneous axillary lymph node (ALN) metas tasis and tended to cause longer mean survival, compared with SH-WBH DOX, The peak of treatment-induced apoptosis was higher for the MTD o f DOX + LL-WBH, compared with SH-WBH + DOX, whereas the apoptosis peak of the MTD of SH-WBH + CDDP was higher than that of LL-WBH + CDDP, Th e most extensive levels of tumor necrosis appeared to occur earlier wi th SH-WBH alone and the MTD of SH-WBH + DOX or CDDP than with other gr oups. Our results suggest that LL-WBH + DOX may be a promising therapy for breast cancer, and the extent of treatment-induced tumor apoptosi s appears to correlate with antitumor response for MTDs of LL-WBH + DO X and SH-WBH + DOX, but not for the MTDs of CDDP with SH-WBH or LL-WBH . (C) 1998 Wiley-Liss, Inc.