This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jiang, B.-Z. Articles by Silber, R. Search for Related Content PubMed PubMed Citation Articles by Jiang, B.-Z. Articles by Silber, R.

Lack of Drug-induced DNA Cross-Links in Chlorambucil-resistant Chinese Hamster Ovary Cells¹

Departments of Medicine and Radiology, New York University School of Medicine, New York, New York 10016 [B-Z. J., B. B. B., T. S., M. P., R. S.], and the Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [Y. H. H.]

Chlorambucil (CLB) is an alkylating agent commonly used in the treatment of several neoplastic disorders. The mechanisms underlying resistance to this drug are not fully defined. We used the DNA alkaline elution technique to study cross-link formation in the wild type (K1) and a CLB-resistant (Chl^R) Chinese hamster ovary cell line. [¹⁴C]CLB was used to measure drug uptake. The CLB-resistant cells were found to have negligible DNA cross-link formation compared to K1 cells at all time points tested. There was a correlation between the resistance to CLB and the decreased ability of resistant cells to form DNA cross-links. Results of drug uptake experiments excluded altered CLB accumulation as the basis for these findings. Assays of O⁶-alkylguanine transferase and topoisomerase II provide evidence against a role of these enzymes in CLB resistance. These studies suggest that the mechanism of CLB cytotoxicity involves the formation of DNA cross-links. Reduced cross-link formation may confer resistance to CLB.

¹ This work was supported by Grant CA11655 from the NIH and by grants from the Winston Foundation and the Marcia Slater Society for Research in Leukemia, Inc.

² Present address: Department of Medicine, UMDNJ - New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103

³ To whom requests for reprints should be addressed, at Department of Medicine, New York University Medical Center, 560 First Avenue, New York, NY 10016.

Received 3/21/89. Revised 6/19/89. Accepted 7/21/89.

This article has been cited by other articles:

				L. Tentori, P. M. Lacal, E. Benincasa, D. Franco, I. Faraoni, E. Bonmassar, and G. Graziani Role of Wild-Type p53 on the Antineoplastic Activity of Temozolomide Alone or Combined with Inhibitors of Poly(ADP-Ribose) Polymerase J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 884 - 893. [Abstract] [Full Text]