The long-term objective of this study is to provide a mechanistic basis for the development of new therapeutic approaches in radiation therapy. We have observed that low doses of radiation can induce several cellular processes that we believe are important in radiation therapy: apoptosis, differentiation, senescence and impaired endothelial cell wound response. Our working hypothesis is that all four of these processes are induced by a limited number of biochemical signals that are produced in irradiated cells. Our objective is to identify these signals and to elucidate the mechanism by which they bring about these cellular responses. The model systems we will use have been selected because they are relevant to radiation therapy and because they allow quantitative single- cell analysis. Apoptosis will be determined by in situ hybridization of PC-3 human prostate cancer cells for expression of the apoptosis marker TRPM-2. Differentiation will be determined by the expression of differentiation-=specific cytokeratins in F9 embryonal carcinoma cells, as a model for retinoic acid-mimetic effects and by laminin expression in retinoic acid treated F9 cells as a model for CAMP-mimetic effects. Senescence will be determined by expression of a senescence-specific fibronectin epitope in normal human fibroblasts (CSC-3-3). The endothelial cell wound healing response will be studied in monolayers of bovine microvascular endothelial cells using digital imaging to measure actin fiber alignment. Two strategies will be employed in our mechanistic studies. The first strategy is to determine the impact of modifiers of DNA damage, protein thiol oxidation and lipid metabolism on the effect of radiation on the regulatory endpoints described above. The second strategy is to use these regulatory endpoints as bioassays to detect bioactive radiation products, or to test potential radiomimetic agents. We will test our multi-signal hypothesis by determining the effect of radiation on the dose response relationship to other signaling agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA046776-04A2
Application #
3190152
Study Section
Radiation Study Section (RAD)
Project Start
1988-03-01
Project End
1996-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Palayoor, S T; Bump, E A; Teicher, B A et al. (1997) Apoptosis and clonogenic cell death in PC3 human prostate cancer cells after treatment with gamma radiation and suramin. Radiat Res 148:105-14
Braunhut, S J; Medeiros, D; Lai, L et al. (1996) Tempol prevents impairment of the endothelial cell wound healing response caused by ionising radiation. Br J Cancer Suppl 27:S157-60
Palayoor, S T; Macklis, R M; Bump, E A et al. (1995) Modulation of radiation-induced apoptosis and G2/M block in murine T-lymphoma cells. Radiat Res 141:235-43
Langley, R E; Quartuccio, S G; Kennealey, P T et al. (1995) Effect of cell cycle stage, dose rate and repair of sublethal damage on radiation-induced apoptosis in F9 teratocarcinoma cells. Radiat Res 144:90-6
Braunhut, S J; Moses, M A (1994) Retinoids modulate endothelial cell production of matrix-degrading proteases and tissue inhibitors of metalloproteinases (TIMP). J Biol Chem 269:13472-9
Langley, R E; Palayoor, S T; Coleman, C N et al. (1994) Radiation-induced apoptosis in F9 teratocarcinoma cells. Int J Radiat Biol 65:605-10
Bump, E A; Braunhut, S J; Palayoor, S T et al. (1994) Novel concepts in modification of radiation sensitivity. Int J Radiat Oncol Biol Phys 29:249-53
Bump, E A; al-Sarraf, R; Pierce, S M et al. (1992) Elevation of mouse kidney thiol content following administration of glutathione. Radiother Oncol 23:21-5
Bump, E A; Cerce, B A; al-Sarraf, R et al. (1992) Radioprotection of DNA in isolated nuclei by naturally occurring thiols at intermediate oxygen tension. Radiat Res 132:94-104