In this application we propose to continue our research into the molecular mechanisms of radiation induced carcinogenesis. We have found that both c-myc and K-ras oncogenes were activated in a panel of large late stage tumors of rat skin induced by a single exposure to ionizing radiation. We have also recently discovered that the activation of c-myc by gene amplification is a late stage event in this model system. The experiments proposed in this application will help to elucidate several important questions in radiation induced cancer, and in carcinogenic mechanisms in general. The major thrust of this proposal is to further clarify the relationship of oncogene activation to the temporal aspects of multistage carcinogenesis in the rat skin model. We will analyze tumor biopsies for activation of myc and ras oncogenes using Southern analysis, PCR and in situ hybridization. These experiments will test the hypothesis that myc activation occurs in a subpopulation of tumor cells, which ultimately enjoys a selective advantage during subsequent progression. The carcinogen and tissue specificities of the oncogene activation patterns we have observed will be determined by comparison with patterns found in tissue block sections of rat skin tumors induced by a chemical carcinogen, and in human skin tumors induced by radiation exposure. Using new applications of the polymerase chain reaction (PCR) methodology for specific sequence amplification, we will determine the earliest time that oncogene activation can be detected in radiation exposed target tissue, before tumor appearance. We have available over 30,000 preserved tissue blocks from 200 experiments dealing with various issues of radiation carcinogenesis. This valuable resource will be tapped to elucidate the relationship of radiation quality with respect to LET to oncogene activation. Radiation induced rat skin tumors will be used for the establishment of cell lines. These lines will be thoroughly characterized including karotype analysis, and will provide useful tools for future research in mechanisms of oncogene activation in radiation carcinogenesis. Increased understanding of the molecular mechanisms associated with skin cancer induced by ionizing radiation will provide useful knowledge for the eventual prevention, management or control of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043199-06
Application #
3185232
Study Section
Radiation Study Section (RAD)
Project Start
1986-07-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Jin, Y; Burns, J; Garte, S J et al. (1996) Infrequent alterations of the p53 gene in rat skin cancers induced by ionizing radiation. Carcinogenesis 17:873-6
Burns, F J; Jin, Y; Garte, S J et al. (1994) Estimation of risk based on multiple events in radiation carcinogenesis of rat skin. Adv Space Res 14:507-19
Felber, M; Burns, F J; Garte, S J (1994) DNA fingerprinting analysis of radiation-induced rat skin tumors. Cancer Biochem Biophys 14:163-70
Roy, N K; Ballesteros, A; Garte, S J (1993) Cloning and sequence of the rat retinoblastoma (Rb) gene cDNA. Nucleic Acids Res 21:170
Burns, F J; Jin, Y; Koenig, K L et al. (1993) The low carcinogenicity of electron radiation relative to argon ions in rat skin. Radiat Res 135:178-88
Garte, S J (1993) The c-myc oncogene in tumor progression. Crit Rev Oncog 4:435-49
Jin, Y; Burns, F J; Garte, S J (1992) Oncogene amplification detected by in situ hybridization in radiation-induced skin cancers in rats. Radiat Res 132:193-9
Felber, M; Burns, F J; Garte, S J (1992) Amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of linear energy transfer and dose. Radiat Res 131:297-301
Burns, F J; Hosselet, S; Jin, Y et al. (1991) Progression and multiple events in radiation carcinogenesis of rat skin. J Radiat Res (Tokyo) 32 Suppl 2:202-16
Garte, S J; Burns, F J (1991) Oncogenes and radiation carcinogenesis. Environ Health Perspect 93:45-9

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