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 treatment-induced apoptosis and necrosis of the maximum tolerated dose (MTD) of doxorubicin (DOX) or cisplatin (CDDP) combined with long-duration, 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 with short-duration, high-temperature WBH (SH-WBH, at 41.5 degrees C for 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 delay in the development of spontaneous axillary lymph node (ALN) metastasis and tended to cause longer mean survival, compared with SH-WBH + DOX. The peak of treatment-induced apoptosis was higher for the MTD of 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. The most extensive levels of tumor necrosis appeared to occur earlier with SH-WBH alone and the MTD of SH-WBH + DOX or CDDP than with other groups. Our results suggest that LL-WBH + DOX may be a promising therapy for breast cancer, and the extent of treatment-induced tumor apoptosis appears to correlate with antitumor response for MTDs of LL-WBH + DOX and SH-WBH + DOX, but not for the MTDs of CDDP with SH-WBH or LL-WBH.
Toyota
N
N
Department of Internal Medicine, The University of Texas Medical School at Houston, USA. toyochan@grape.med.tottori-u.ac.jp
Strebel
F R
FR
Stephens
L C
LC
Matsuda
H
H
Oshiro
T
T
Jenkins
G N
GN
Bull
J M
JM
D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D005069:Evaluation Studies as Topic; D006979:Hyperthermia, Induced; D007700:Kinetics; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009336:Necrosis; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D004317:Doxorubicin; D002945:Cisplatin