Epidemiological evidence has shown that ionizing radiation in man is a carcinogen with a relatively long latency period. Evidence is also emerging to indicate that patients with a history of prior irradiation of benign or malignant lesions are at increased risk of developing subsequent neoplasms. The long latency period could be explained by the initiating potential of ionizing radiation followed by promotion of benign and malignant tumors, and ionizing radiation may have the ability to convert benign tumors to malignant tumors. To date these important questions have not been directly addressed experimentally. Therefore the overall goal of this proposal is to investigate the initiating potential of ionizing radiation in the classical mouse, two-stage model of carcinogenesis and to investigate the activation of the ras family of oncogenes in radiation-induced tumors. The biological questions being asked in this proposal include: 1) Can it be shown that ionizing radiation has initiating potential in mouse skin by studying the ability of the agent 12-0-tetradecanoylphorbol-13-acetate (TPA) to promote skin tumors in mice treated with a single subcarcinogenic dose of ionizing radiation? 2) Can ionizing radiation act to enhance the rate of conversion of benign papillomas to malignant squamous cell carcinomas in MNNG initiated and TPA promoted animals? In parallel molecular studies the following questions would be asked: 1) In ionizing radiation-induced skin tumors, what member of the ras family of oncogenes (Ha-ras, K-ras, N-ras) can be shown to be activated using the NIH/3T3 transfection assay? 2) What specific base mutations are responsible for ras activation? (By isolating, cloning, and then sequencing both the normal and activated ras genes) The activation of Ha-ras has been found in chemically initiated skin tumors, but nothing is known about which ras gene is activated or what mutations are responsible for activation in radiation-initiated tumors. Potential differences in the chemical and radiation-activated ras genes and between chemical versus radiation-induced mutations in the ras genes may help in future studies of human tumors in which investigators may attempt to identify etiological factors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042239-03
Application #
3183242
Study Section
Radiation Study Section (RAD)
Project Start
1986-08-01
Project End
1990-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Gupta, A; Andrews, K L; McDaniel, K M et al. (1999) Experimental induction of rhabdomyosarcoma in mice with fractionated doses of beta-irradiation. J Cancer Res Clin Oncol 125:257-67
Domann Jr, F E; Levy, J P; Finch, J S et al. (1994) Constitutive AP-1 DNA binding and transactivating ability of malignant but not benign mouse epidermal cells. Mol Carcinog 9:61-6
Domann, F E; Levy, J P; Birrer, M J et al. (1994) Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice. Cell Growth Differ 5:9-16
Bowden, G T; Schneider, B; Domann, R et al. (1994) Oncogene activation and tumor suppressor gene inactivation during multistage mouse skin carcinogenesis. Cancer Res 54:1882s-1885s
Bowden, G T; Nelson, M A; Levy, J P et al. (1993) Molecular mechanisms of skin carcinogenesis induced by chemicals and ionizing radiation. Recent Results Cancer Res 128:215-30
Finch, J; Andrews, K; Krieg, P et al. (1991) Identification of a cloned sequence activated during multi-stage carcinogenesis in mouse skin. Carcinogenesis 12:1519-22
Bowden, G T; Ostrowski, L E; Bonham, K et al. (1991) Differential gene expression during tumor promotion and progression in the mouse skin model. Basic Life Sci 57:127-40;discussion 140-1
Bowden, G T; Krieg, P (1991) Differential gene expression during multistage carcinogenesis. Environ Health Perspect 93:51-6
Matrisian, L M; Bowden, G T (1990) Stromelysin/transin and tumor progression. Semin Cancer Biol 1:107-15
Bowden, G T; Jaffe, D; Andrews, K (1990) Biological and molecular aspects of radiation carcinogenesis in mouse skin. Radiat Res 121:235-41

Showing the most recent 10 out of 14 publications