Hyperthermia in the febrile (> or = 41 degrees C) and therapeutic ranges (< or = 42 degrees C) may alter antitumor host defenses. Understanding the regulatory influences of hyperthermia on various host defense mechanisms will have increasing importance as BRMs use expands and we ask if hyperthermia can be used effectively with these agents. Activated monocytes/macrophages in particular appear to have great potential as effectors for BRM therapy and appropriate use of hyperthermia may enhance this potential, but the effect of hyperthermia on macrophage actions against tumor cells has not been systematically examined. We proposed to use various rodent and human sources of monocytes/macrophages and tumor cells and to study the effect of hyperthermia on various macrophage cytotoxic actions against tumor cells in vitro.
The Specific Aims are: (1) to determine if heating monocytes/macrophages alters their ability to execute various cytotoxic functions against unheated tumor cells in coculture. Conversely, does heating tumor cells alter their response to the cytotoxic actions of unheated effector cells in co-culture? (2) To ask if heated-monocyte/macrophage production of soluble cytotoxic mediators is altered, and if heating perturbs tumor cell responses to these mediators so that the net cytotoxic outcome can be optimized (3) To determine if heating monocytes/macrophages alters their ability to respond to priming and triggering signals. Conversely, does heating tumor cells activate or enhance activation of macrophages in coculture. (4) To ask if heating of monocytes/macrophages or target cells alters the selectivity of the tumoricidal reaction vis-a-vis tumor vs normal targets. (5) To determine the temporal relationships between heating of tumor cells and co- culture with monocytes/macrophages or their mediators on the cytotoxic manifestations. (6) To ask if thermotolerance protects tumor cells from monocytes/macrophages and their mediators. Conversely, can these effector cells develop thermotolerance to heat effects on their cytotoxic actions? (7) To investigate the mechanisms by which hyperthermia alters the effector cell arm of tumor necrosis factor (TNF) cytotoxic pathways. The ultimate objective of this proposal is to use answers to the above questions to help optimize the adjunctive use of hyperthermia with protocols designed to use either appropriately activated monocytes/macrophages or cytotoxic monokines in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047786-05
Application #
2092744
Study Section
Radiation Study Section (RAD)
Project Start
1989-12-01
Project End
1995-06-30
Budget Start
1993-12-01
Budget End
1995-06-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Klostergaard, J; Leroux, M E; Auzenne, E et al. (2006) Hyperthermia engages the intrinsic apoptotic pathway by enhancing upstream caspase activation to overcome apoptotic resistance in MCF-7 breast adenocarcinoma cells. J Cell Biochem 98:356-69
Leroux, E; Auzenne, E; Weidner, D et al. (2001) Febrile and acute hyperthermia enhance TNF-induced necrosis of murine L929 fibrosarcoma cells via caspase-regulated production of reactive oxygen intermediates. J Cell Physiol 187:256-63
Wang, G; Klostergaard, J; Khodadadian, M et al. (1996) Murine cells transfected with human Hsp27 cDNA resist TNF-induced cytotoxicity. J Immunother Emphasis Tumor Immunol 19:9-20
Klostergaard, J; Akimaru, Y; Tomasovic, S P (1996) Step-down heating enhances the cytotoxicity of human tumour necrosis factor on murine and human tumour cell lines in vitro. Int J Hyperthermia 12:97-114
Klostergaard, J; Leroux, M E; Tomasovic, S P (1995) Clonogenic survival studies of human colon tumor cell lines in vitro: combined hyperthermia, 5-fluorouracil/leucovorin, carboplatin and tumor necrosis factor. Radiat Res 141:44-8
Tomasovic, S P; Khodadadian, M; Hung, M C et al. (1994) Hyperthermia enhances the cytotoxicity of National Institutes of Health 3T3 cells transfected with a noncleavable transmembrane pro-tumor necrosis factor deletion mutant. J Immunother Emphasis Tumor Immunol 16:181-7
Tomasovic, S P; Vasey, T A; Story, M D et al. (1994) Cytotoxic manifestations of the interaction between hyperthermia and TNF: DNA fragmentation. Int J Hyperthermia 10:247-62
Tomasovic, S P; Lu, S; Klostergaard, J (1992) Comparative in vitro studies of the potentiation of tumor necrosis factor (TNF)-alpha, TNF-beta, and TNF-SAM2 cytotoxicity by hyperthermia. J Immunother (1991) 11:85-92
Klostergaard, J; Leroux, E; Siddik, Z H et al. (1992) Enhanced sensitivity of human colon tumor cell lines in vitro in response to thermochemoimmunotherapy. Cancer Res 52:5271-7
Tomasovic, S P; Klostergaard, J (1991) Bacterial endotoxin lipopolysaccharide modulates synthesis of the 70 kDa heat stress protein family. Int J Hyperthermia 7:643-51