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Differences in DNA Alkylation Products Formed in Sensitive and Resistant Human Glioma Cells Treated with N-(2-Chloroethyl)-N-nitrosourea¹

Brain Tumor Research Center of the Department of Neurological Surgery, University of California, San Francisco, California 94143 [W. J. B., K. T.]; and Department of Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 [D. B. L.]

The distribution of alkylated deoxynucleosides and bases has been determined in the DNA of a sensitive and a resistant human gliomaderived cell line exposed to therapeutic levels of [³H]N-(2-chloroethyl)-N-nitrosourea in vitro. The resistant cell line is 5-fold less sensitive to the cytotoxic effects of N-(2-chloroethyl)-N-nitrosourea and 8-fold less sensitive to sister chromatid exchange than the sensitive cell line. In comparison with the sensitive cells, DNA from the resistant cells contains much less of the cross-link, 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane. DNA from the resistant cells also contains significantly fewer minor base modifications. The decrease in 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane cross-link formation is probably explained by the higher level of O⁶-alkyltransferase in the resistant cell line. The lower levels of other DNA modifications could be explained by the presence of higher levels of other DNA repair activities.

¹ Supported by Grants CA-13525 and CA-44499 from the National Cancer Institute. Presented in part at the 78th Annual Meeting of the American Association for Cancer Research, May 1987, Atlanta, GA (24).

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655.

Received 2/26/88. Revised 5/11/88. Accepted 5/20/88.

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