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Studies on DNA Repair in Human Lymphocytes Treated with Proximate Carcinogens and Alkylating Agents¹

Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213

The incorporation of thymidine into DNA by human peripheral blood lymphocytes after exposure to alkylating agents or proximate carcinogens was used to investigate presumed DNA repair in a nondividing human cell system. In the presence of hydroxyurea, which was used to suppress the "background" DNA synthesis in the rare cell in S phase, lymphocyte cultures treated with nitrogen mustard, methyl methanesulfonate, or ethyl methanesulfonate, or with two proximate carcinogens, ß-propiolactone or N-acetoxy-2-acetylaminofluorene, incorporated from 4 to 9 times as much thymidine as did controls. Autoradiographs indicated that about 90% of the lymphocytes participated in this response in contrast to the control preparations in which no more than 0.1 to 0.2% of the cells showed labeling with thymidine. Preparation of DNA by isopycnic centrifugation in CsCl and digestion with snake venom phosphodiesterase was used to show that thymidine was actually incorporated into DNA and that less than 20% of this incorporation could be accounted for by terminal addition. No stimulation was noted with the precarcinogens dimethylnitrosamine, 3'-methyl-4-dimethylaminoazobenzene, and 2-acetylaminofluorene or with iodoacetamide which alkylates protein but not DNA. Electron micrographs of cells 15 hr after treatment with nitrogen mustard or methyl methanesulfonate showed considerable evidence of cellular damage, marked especially by separation of the inner and outer nuclear membranes. Very little if any damage was seen with N-acetoxy-2-acetylaminofluorene.

¹ This is Paper I of the series, "Studies on DNA Repair in Carcinogenesis." Work was supported by grants from the Health Research and Services Foundation, Pittsburgh, Pa. (M-68), the American Cancer Society (E-129M and IN-58H), and NIH (CA-06074 from the National Cancer Institute and AI-07125 from the National Institute of Allergy and Infectious Diseases).

² Sarah Mellon Scaife Fellow in Pathology.

³ Present address: Fels Research Institute, Temple University School of Medicine, Philadelphia, Pa. 19140.

⁴ Present address: Department of Pathology, University of California School of Medicine, La Jolla, Calif. 92037.

Received 2/26/71. Accepted 5/12/71.

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