Molecular, cellular and clinical abnormalities in patients with xeroderma pigmentosum (XP), with Cockayne syndrome (CS), and with Bloom's syndrome (BS) are being studied. We developed new assays using plasmids as tools to measure DNA repair, DNA end joining, and mutagenesis at the molecular level in cultured human cells. The DNA repair and replication systems in both lymphoblastoid cells and fibroblasts from the same XP patient induced more mutations into the UV treated shuttle vector plasmid, pZl89, than normal controls. There was an additional mutagenic hotspot in the plasmid passed through the XP lymphoblasts not seen with the XP fibroblasts. This demonstrates variability of mutagenic hotspots with different cell types. CS cells had reduced repair of cyclobutane dimer type photoproducts in the UV treated plasmid but normal repair of non-dimer photoproducts. Bloom's syndrome cells were shown to have normal levels of topoisomerase II activity despite increased spontaneous chromosome breakage. The mutagenic properties of cytochrome P450 activated carcinogens in repair deficient human cells is being studied. Immune studies revealed reduced natural killer (NK) cell activation and impaired interferon production in XP patients. A registry of XP patients has been established. We found high dose (2 mg/kg/da) oral 13-cis retinoic acid to be effective in preventing skin cancers in XP patients but very toxic. A variable response to low dose (0.5 mg/kg/da) oral 13-cis retinoic acid was found in different patients ranging from almost complete tumor prevention to no beneficial effect.
