Hyperthermia significantly increases chemotherapy induced cytotoxicity for both tumor and normal tissue. Thus, normal tissue injury limits the application of this powerful anti-cancer therapy. in the light of this serious restriction to a potentially effective therapy, there are surprisingly few studies of acute normal tissues reaction to chemotherapy with either local/regional or systemic heat, and no studies of late normal tissue response. The general objective of this continuing research is to establish an optimal thermo-chemotherapy treatment regiment that provides both minimal injury to normal tissue with maximum tumor ablation. The response of a rat fibrosarcoma will be used as a tumor model. We hypothesize that known vascular, metabolic, pH and repair differences between tumors and normal tissues may be exploited to reduce normal tissue damage while maintaining anti-tumor effect. We propose to utilize these dissimilarities between tumor and normal tissues by first establishing dose response curves of local/regional and systemic heat administered simultaneously with the single agents cisplatin, doxorubicin, bleomycin and their respective less toxic analogs. We will first quantitate normal tissue response to the thermochemotherapy; we will then use pharmacokinetic and biochemical pharmacologic studies to optimize drug/heat schedules in order to reduce normal tissue toxicities, retain anti-tumor efficacy of the combined therapy in sensitive tumors and demonstrate activity against resistant tumors. Protective compounds known to reduce specific drug toxicities at normal temperature will then be tested with hyperthermia and drugs to further increase the therapeutic index of the combined modality therapy. Information learned from these studies will be applied to the rational design of a multi-agent chemotherapy-hyperthermia therapy to be used in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043090-05
Application #
3185009
Study Section
Radiation Study Section (RAD)
Project Start
1986-07-15
Project End
1994-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Rowe, R Wanda; Strebel, Frederick R; Proett, Jesse M et al. (2010) Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model. Int J Hyperthermia 26:565-76
Rowe, R Wanda; Tomoda, Masaaki; Strebel, Frederick R et al. (2004) The natural progression of microvasculature in primary tumor and lymph node metastases in a breast carcinoma model: relationship between microvessel density, vascular endothelial growth factor expression, and metastatic invasion. Cancer Biol Ther 3:408-14
Sumiyoshi, K; Strebel, F R; Rowe, R W et al. (2003) The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases. Int J Hyperthermia 19:103-18
Toyota, N; Strebel, F R; Stephens, L C et al. (1998) Therapeutic efficacy and apoptosis and necrosis kinetics of doxorubicin compared with cisplatin, combined with whole-body hyperthermia in a rat mammary adenocarcinoma. Int J Cancer 76:499-505
Toyota, N; Strebel, F R; Stephens, L C et al. (1998) 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. Oncol Rep 5:1231-6
Toyota, N; Strebel, F R; Stephens, L C et al. (1997) Long-duration, mild whole body hyperthermia with cisplatin: tumour response and kinetics of apoptosis and necrosis in a metastatic rat mammary adenocarcinoma. Int J Hyperthermia 13:497-506
Matsuda, H; Strebel, F R; Kaneko, T et al. (1997) Long duration-mild whole body hyperthermia of up to 12 hours in rats: feasibility, and efficacy on primary tumour and axillary lymph node metastases of a mammary adenocarcinoma: implications for adjuvant therapy. Int J Hyperthermia 13:89-98
Makino, M; Lodato, R F; Stephens, L C et al. (1996) Protective effect of NG-monomethyl-L-arginine against hypotension inducted by combined tumour necrosis factor-alpha and whole body hyperthermia in rats. Int J Hyperthermia 12:617-34
Sakaguchi, Y; Stephens, L C; Makino, M et al. (1995) Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. Cancer Res 55:5459-64
Wondergem, J; Strebel, F R; Stephens, L C et al. (1995) Chronic effect of whole-body hyperthermia combined simultaneously with cis-diamminedichloroplatinum (II) on normal tissue in rat. Int J Hyperthermia 11:37-47

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