We have characterized x-ray induced hypermutability and have observed two new additional manifestations of hypersensitivity. These three observations together suggest that induced hypersensitivity may be a basic and general phenomenon that occurs when cells are treated with x-rays as well as other DNA damaging agents. Treated cells and their progeny appear to be rendered susceptible to subsequent exposure to certain chemicals and radiations that damage DNA or induce changes in template structure or activity. We now propose to test the hypothesis that induced hypersensitivity is a general phenomenon whose characteristics make it relevant to multistage carcinogenesis. We will determine the characteristics of induced hypersensitivity in vivo. Our experimental procedures will concentrate on x-rays as an initiator of hypersensitivity but will use comparisons between x-rays and other carcinogens, between human and rodent cells and between effects on cancer-prone and normally responsive rats to assess the potential relevance of hypersensitivity to the cancer process. We will determine whether the three indicators of hypersensitivity are manifestations of the same underlying process by concommitant measurement of their variation when several parameters, known to modify the biological response of x-rays, are manipulated. Special attention will be given to the potency of multiple low doses to induce the effect, because of the similarity to human exposure patterns. We will also evaluate the presence of the hypersensitive state in cells derived from human beings who are cancer prone due to genetic condition or prior carcinogen exposure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039543-02
Application #
3178633
Study Section
Radiation Study Section (RAD)
Project Start
1984-09-01
Project End
1990-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Munshi, N C; Williams, J R (1994) Effect of tumor irradiation on the uptake of lymphokine-activated killer cells in a murine tumor model. Cancer Res 54:1657-9
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Liou, S H; Jacobson-Kram, D; Poirier, M C et al. (1989) Biological monitoring of fire fighters: sister chromatid exchange and polycyclic aromatic hydrocarbon-DNA adducts in peripheral blood cells. Cancer Res 49:4929-35
Dillehay, L E; Jacobson-Kram, D; Williams, J R (1989) DNA topoisomerases and models of sister-chromatid exchange. Mutat Res 215:15-23
Xiao, S Q; Jacobson-Kram, D; Piantadosi, S et al. (1989) Increased chromosomal radiosensitivity in patients undergoing radioimmunoglobulin therapy. Mutat Res 227:39-45
D'Arpa, P; Dillehay, L E; Opishinski, J W et al. (1989) Heritable hypersensitivity to induced mutagenesis in the progeny of cell populations exposed to UVC (254 nm). Radiat Res 117:163-9
Chang, G; Jacobson-Kram, D; Williams, J R (1988) Use of an established human hepatoma cell line with endogenous bioactivation for gene mutation studies. Cell Biol Toxicol 4:267-79
Dillehay, L E; Denstman, S C; Williams, J R (1987) Cell cycle dependence of sister chromatid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells. Cancer Res 47:206-9
Lim, M; Jacobson-Kram, D; Bowman, R E et al. (1987) Effect of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on sister chromatid exchange levels in peripheral lymphocytes of the rhesus monkey. Cell Biol Toxicol 3:279-84
Shubber, E K; Jacobson-Kram, D; Williams, J R (1986) Comparison of the Ames assay and the induction of sister chromatid exchanges: results with ten pharmaceuticals and five selected agents. Cell Biol Toxicol 2:379-99

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