Abstract
We investigated the ability of nine fibroblast cell strains from patients with the hereditary from 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 γ-radiation, which causes DNA scission; actinomycin D, a DNA-intercalating agent; and mitomycin C, a bifunctional alkylating agent leading to DNA-DNA crosslinking. 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 µg/ml in the nine normal strains and D0 values of 0.016–0.067 µg/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 µg/ml versus 0.19–0.66 µg/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.
Footnotes
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↵2 Supported in part by Grant EY04612 from the U.S. National Eye Institute (NIH), the Vikings Children's Fund, and the Children's Cancer Research Fund of the University of Minnesota. To whom requests for reprints should be addressed, at Box 454, Mayo Building, University of Minnesota, Minneapolis, MN 55455.
- Received February 24, 1986.
- Revision received July 14, 1986.
- Accepted September 4, 1986.
- ©1986 American Association for Cancer Research.