In vitro sensitivity of normal and hereditary retinoblastoma fibroblasts to DNA-damaging agents.
We investigated the ability of nine fibroblast cell strains from patients with the hereditary form of retinoblastoma (RB) to handle various types of DNA-damaging agents and compared the results with those obtained in nine normal strains. Cell strains were exposed to gamma-radiation, which causes DNA scission; actinomycin D, a DNA-intercalating agent; and mitomycin C, a bifunctional alkylating agent leading to DNA-DNA cross-linking. Cell strains were studied for their ability to survive in a cytotoxicity assay. Nine normal strains exhibited a mean D0 (inverse of the slope of the straight line portion of the survival curve) of 134-178 cGy after radiation exposure, compared to a range of 119-186 cGy in the nine RB strains (P = 0.33). Similarly, exposure to actinomycin D led to D0 values of 0.024-0.069 microgram/ml in the nine normal strains and D0 values of 0.016-0.067 microgram/ml in the RB strains (P = 0.64). The nine RB strains did exhibit a small overall increase in sensitivity after exposure to mitomycin C, with D0 values ranging from 0.14-0.32 microgram/ml versus 0.19-0.66 microgram/ml in the nine normal strains (P = 0.002); however, when the two most resistant normal strains were excluded from analysis, results were similar. Three RB cell strains derived from individuals who had either developed second cancers or who had a family history of additional sarcomas consistently exhibited increases in sensitivity to all three DNA-damaging agents studied compared with other hereditary RB cell strains as well as normal strains. The results suggest that normal human fibroblast cell strains exhibit a wide response to DNA-damaging agents, especially chemical agents. Most hereditary RB strains exhibit sensitivity well within the normal range; however, strains from RB patients predisposed to second cancers exhibit increases in sensitivity to DNA-damaging agents. The heterogeneous ability to repair DNA damage may play a role in the development of second malignant neoplasms in hereditarily predisposed individuals.
D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D003609:Dactinomycin / Q000494:pharmacology; D005134:Eye Neoplasms / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology; D009369:Neoplasms / Q000209:etiology; D012175:Retinoblastoma / Q000235:genetics*
D008937:Mitomycins; D003609:Dactinomycin; D016685:Mitomycin; D004247:DNA