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.
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