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Synergistic Cytotoxicity and DNA Strand Break Formation by Bromodeoxyuridine and Bleomycin in Human Tumor Cells¹

Lynn Sage Clinical Pharmacology Laboratory, Joint Section of Hematology/Oncology [S. P. A., R. L. S.] and Joint Department of Radiation Oncology [M. A. B., R. R. W.], University of Chicago and Michael Reese Medical Centers, Chicago, Illinois 60616

5-Bromo-2'-deoxyuridine (BrdUrd) is a thymidine analogue whose cellular effects are related to its incorporation into DNA. BrdUrd is a known radiosensitizing agent that could potentially enhance the activity of chemotherapeutic agents that interact directly with DNA. Therefore we studied the interaction of BrdUrd and bleomycin in a human head and neck squamous carcinoma cell line, SQ20B. Using a colony-forming assay and analyzing results by the median-effect method, we have shown that there is synergistic cytotoxicity between BrdUrd and bleomycin. Synergism is evident when BrdUrd is administered prior to bleomycin or when the two drugs are applied simultaneously and is evident at a variety of BrdUrd:bleomycin concentration ratios. Alkaline elution of DNA from cells exposed to BrdUrd and bleomycin demonstrated greater single strand break formation than expected from the individual single strand break frequencies induced by each drug alone. BrdUrd did not affect the rate of repair of bleomycin-induced single strand breaks or the formation of double strand breaks. Although the mechanism of this interaction at the molecular level is unclear, our studies suggest that a direct interaction of bleomycin with BrdUrd-substituted DNA may be the cause of the synergism of these two agents.

¹ Supported in part by Cancer Research Foundation of Chicago, and The American Cancer Society (Illinois Division).

² To whom requests for reprints should be addressed, at Oncology Unit, Mater Misericordiae Hospital, Waratah, N.S.W. 2298, Australia.

Received 7/ 2/87. Revised 11/18/87. Revised 2/ 3/88. Revised 4/ 5/88. Accepted 5/ 2/88.

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