Molecular, cellular and clinical abnormalities are being studied in 3 genetic diseases with cellular hypersensitivity to environmental agents: xeroderma pigmentosum (XP), Cockayne's syndrome (CS) and dysplastic nevus syndrome (DNS) of familial melanoma. We developed new assays to measure DNA repair and mutagenesis at the molecular level in human cells. CS cells had increased mutability of plasmids with cyclobutane dimer photoproducts but normal repair of non-dimer photoproducts. These abnormalities in repair of different photoproducts may be linked to the increased frequency of skin cancer in XP but normal cancer frequency in CS. We found that introduction of cloned DNA repair genes substantially corrected the UV mutagenic defect in XP-D and XP-A cells. XP-D and XP-A fibroblasts containing transfected ERCC2 and XPAC genes, respectively, were found to have increased repair and decreased mutagenesis of UV- treated plasmids. Normal lymphoblastoid cells showed increased plasmid UV mutability with increasing donor age. DNS lymphoblastoid cell lines were found to have abnormally elevated mutability of UV-treated plasmids, a possible cellular marker for this genetic disorder. Long-term study of chemoprevention of skin cancer in XP with oral 13-cis retinoic acid (RA) (Accutane) showed that high dose (2 mg/kg/da) 13-cis RA was effective in preventing skin cancers but very toxic, and that low dose (0.5 mg/kg/da) drug gave a variable response in different patients ranging from almost complete tumor prevention to no beneficial effect. XP patients were shown to have defective production of interferon in vitro, an immune defect that may play a role in their increased cancer susceptibility. Therapeutic injection of intralesional interferon resulted in marked clearing of melanoma in situ lesions in one XP patient. The anatomic location of skin cancers in XP patients indicates that although UV exposure causes both melanoma and non-melanoma cancer, the mechanism of skin cancer induction is different for each type of cancer.
