HYPERRESISTANCE TO 4-NITROQUINOLINE 1-OXIDE CYTOTOXICITY AND REDUCED DNA-DAMAGE FORMATION IN DERMAL FIBROBLAST STRAINS DERIVED FROM 5 MEMBERS OF A CANCER-PRONE FAMILY

Dermal fibroblasts cultured from members of a family presenting multip le polyps and sarcomas were compared with fibroblast strains from unre lated healthy donors for sensitivity to killing by four genotoxic agen ts. Cells from the sister of the male proband (strain 3437T), mother ( strain 3703T), two of his paternal aunts (3701T and 3704T) and one pat ernal uncle (3702T) displayed marked resistance (1.8 to 4.3 times grea ter than the normal mean) to 4-nitroquinoline 1-oxide (4NQO), a procar cinogen whose DNA-damaging properties encompass those of both far (254 nm) ultraviolet (UV) light and ionising radiation. These same 4NQO-re sistant cells, however, responded normally to reproductive inactivatio n by UV light, Co-60 gamma radiation or the alkylating agent methylnit rosourea, signifying that the abnormal resistance of these cells to 4N QO is not associated with aberrant DNA metabolism. In keeping with thi s conclusion, exposure to a given dose of 4NQO produced decreased amou nts of DNA damage and stimulated lower levels of repair DNA synthesis in all five 4NQO-resistant strains than in normal controls. Moreover, exogenous radiolabelled 4NQO accumulated to a lesser extent in the 4NQ O-resistant than in the normal fibroblasts. Cell sonicates of strains 3437T, 3701T and 3702T exhibited reduced capacities (40-60% of normal) to catalise the conversion of 4NQO to the proximate carcinogen 4-hydr oxyaminoquinoline 1-oxide. However, the 4NQO-resistant strains 3703T a nd 3704T carried out 4NQO bioreduction at normal rates. Our data there fore indicate that enhanced resistance to 4NQO cytotoxicity in 3437T, 3701T and 3702T is a consequence of anomalies in both intracellular ac cumulation and enzymatic reduction of 4NQO, whereas 4NQO resistance in 3703T and 3704T appears to result solely from reduced intracellular d rug accumulation.