Abstract

The aim of the project is to investigate the role of intracellular-free calcium in the response to cells to hyperthermia. Experiments are designed to determine the effect of clinically relevant heating doses on cell Ca2+ concentrations and to elucidate the subcellular origins of heat-induced Ca2+ increase. Studies will further trace the mechanisms involved in the mobilization of Ca2+ from internal pools. Effects on membrane phosphoinositides and on mitochondrial and endoplasmic reticulum Ca2+ gating will be explored. Events distal to cell Ca2+ increases including activation of protein kinases, proteases and phospholipases will be investigated in an effort to gain an understanding of the role of Ca2+ in pathways of thermal cell killing. Changes in ion concentration and enzyme activities will be correlated with parallel studies on clonogenicity. The ultimate purpose of the study is to gain a clearer understanding of the mechanism of hyperthermic killing. This may permit a more rational application of hyperthermia alone and in combination with other treatments. In addition, a role for Ca2+ some classes of active drugs which are not currently used for cancer treatment will be tested in the study.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29CA044940-02
Application #
3458204
Study Section
Radiation Study Section (RAD)
Project Start
1988-06-01
Project End
1992-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Calderwood, S K; Stevenson, M A; Price, B D (1993) Activation of phospholipase C by heat shock requires GTP analogs and is resistant to pertussis toxin. J Cell Physiol 156:153-9
Calderwood, S K; Stevenson, M A (1993) Inducers of the heat shock response stimulate phospholipase C and phospholipase A2 activity in mammalian cells. J Cell Physiol 155:248-56
Bruce, J L; Price, B D; Coleman, C N et al. (1993) Oxidative injury rapidly activates the heat shock transcription factor but fails to increase levels of heat shock proteins. Cancer Res 53:12-5
Tishler, R B; Calderwood, S K; Coleman, C N et al. (1993) Increases in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents. Cancer Res 53:2212-6
Price, B D; Calderwood, S K (1993) Increased sequence-specific p53-DNA binding activity after DNA damage is attenuated by phorbol esters. Oncogene 8:3055-62
Price, B D; Mannheim-Rodman, L A; Calderwood, S K (1992) Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. J Cell Physiol 152:545-52
Price, B D; Calderwood, S K (1992) Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins. Cancer Res 52:3814-7
Price, B D; Calderwood, S K (1992) Heat-induced transcription from RNA polymerases II and III and HSF binding activity are co-ordinately regulated by the products of the heat shock genes. J Cell Physiol 153:392-401
Bader, S B; Price, B D; Mannheim-Rodman, L A et al. (1992) Inhibition of heat shock gene expression does not block the development of thermotolerance. J Cell Physiol 151:56-62
Lam, K T; Calderwood, S K (1992) hsp70 binds specifically to a peptide derived from the highly conserved domain (I) region of p53. Biochem Biophys Res Commun 184:167-74

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