Cultures of skin fibroblasts and peripheral lymphocytes from normal and cancer-prone individuals, as well as neoplastic cells transformed in culture or in vivo, are utilized in evaluating the relationship between radiation-induced chromosomal DNA damage, deficient DNA repair, cancer susceptibility and malignant neoplastic transformation. An increased incidence of chromatid damage after x-irradiation during the G-2 phase of the cell cycle is associated with both a predisposition to cancer and malignant transformation and can provide the basis of a test for cancer susceptibility. A genetic basis for this radiosensitivity with localization of genes to specific chromosomes is indicated from studies with somatic cell hybrids, inbred strains of mice, and congenic mouse strains. The chromosomal radiosensitivity appears to result from deficient DNA repair during G-2. Another aspect of this project is to develop a reproducible transformation system with human epidermal keratinocytes as an in vitro model for following the progression of biologic and biochemical changes leading to neoplastic transformation. An associated problem is to identify quantifiable cytomorphologic changes diagnostic of neoplastic transformation to facilitate transfection and transformation studies.
