The contribution of sunlight to risk of developing malignant/melanoma is poorly understood, in sharp contrast to its contribution to basal and squamous cell carcinoma which is direct and cumulative over the life span of an individual and there is an epidemiological link with exposure to the chemical industry. There is an hereditary form of cutaneous malignant melanoma (HCMM) which appears to be inherited as an autosomal dominant trait. The majority of HCMM patients have clinically and histologically distinct, preneoplastic melanocyte abnormalities, dysplastic nevus syndrome (DNS) which are correlated with a markedly increased risk of developing malignant melanoma. We recently found that non-malignant skin fibroblasts from several HCMM/DNS patients are abnormally sensitive to the cytotoxic and mutagenic effects of 4-nitroquinoline-1-oxide (4NQO), a UV-mimetic carcinogen. Others have detected an abnormally increased sensitivity of such cells to killing by UV light (254 nm). If this abnormal sensitivity to mutagenicity by carcinogens were characteristic of cells from the majority of such patients, this could provide insight into the etiology of the disease. 1. We propose to compare fibroblasts from HCMM/DNS patients, representing various families which have been studied in depth by the N.C.I. with normal cells for sensitivity to the cytotoxic and mutagenic effects of 4NQO and simulated sunlight. 2. We will determine if individuals from HCMM/DNS families whose fibroblasts are hypersensitive to 4NQO and/or simulated sunlight have lymphoid cells that are also hypersensitive. 3. Using radioactive labeled 4NQO, as well as intermediate and ultimate reactive metabolites of this carcinogen, we will investigate the biochemical basis for the increased sensitivity. a. We will determine if it reflects altered metabolic activation leading to increased levels of DNA damage. If so, we will see if this characteristic extends to environmental carcinogens which are activated by pathways similar to 4NQO. b. We will determine if it reflects decreased rates of repair of DNA damage formed by 4NQO. If so, we will see if this characteristic extends to other environmental carcinogens, structurally related to 4NQO. 4. We will test the most sensitive cells for sensitivity to neoplastic transformation induced by these agents.
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| Sato, K; Howell, J N; Greene, M H et al. (1988) Relationship between sensitivity of cells from patients with hereditary cutaneous malignant melanoma to killing and mutations by 4-nitroquinoline 1-oxide and adduct formation. Cancer Res 48:5145-50 |
