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The Role of O⁶-Alkylguanine DNA Alkyltransferase in Limiting Nitrosourea-induced Sister Chromatid Exchanges in Proliferating Human Lymphocytes¹

Division of Hematology Oncology, Department of Medicine, Cleveland Metropolitan General Hospital, Cleveland, Ohio 44109 [J.E.T.] and Hematology Oncology Division, Department of Medicine, R. L. Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 [S.L.G.]

Although induction of sister chromatid exchanges (SCEs) following nitrosourea exposure may be greater during cell proliferation, the increase could be offset by the action of the DNA repair protein O⁶-alkylguanine DNA alkyltransferase (alkyltransferase). To evaluate these factors in resting and proliferating (phytohemagglutinin stimulated) human lymphocytes, we studied the effect of changes in alkyltransferase activity on 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced SCEs. Phytohemagglutinin stimulation resulted in induction of alkyltransferase activity (5.9 ± 0.3 units, resting, versus 9.2 ± 0.2 units, proliferating). In both resting and proliferating lymphocytes the alkyltransferase activity was inactivated by 85–88% after an 18-h exposure to 0.5 mM of the modified base O⁶methylguanine (O⁶mGua). However, 48 h after removal of O⁶mGua, proliferating lymphocytes recovered alkyltransferase activity while resting cells did not. In the absence of O⁶mGua, both resting and proliferating lymphocytes were equally sensitive to BCNU-induced SCEs. Following inactivation of the alkyltransferase by O⁶mGua, BCNU-induced SCEs were markedly increased, but the increase was much greater in resting than proliferating cells, 4-fold vs. 2.6-fold at each dose of BCNU (P < 0.001). The factors providing partial protection against BCNU-induced SCEs in proliferating lymphocytes appear to include the proliferation-dependent increase in alkyltransferase activity and the ability of proliferating lymphocytes to rapidly recover alkyltransferase activity after its inactivation. Thus, the alkyltransferase appears to provide an important mechanism of resistance to SCE induction in human lymphocytes.

¹ Supported by the American Cancer Society, Ohio Division, Cuyahoga County Branch, and Grants CA-07912, CA-43688, P30-CA-43703 from the National Cancer Institute and ES-00134 from the National Institute of Environmental Health Sciences.

² To whom requests for reprints should be addressed, at Cleveland Metropolitan General Hospital, Highland View Hospital, 3395 Scranton Road, Cleveland, OH 44109.

³ Recipient of a Mallinckrodt Scholar Award.

Received 7/15/88. Revised 12/22/88. Accepted 1/20/89.

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