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Effect of Retinoic Acid on DNA Cleavage and Cytotoxicity of Topoisomerase II-reactive Drugs in a Human Head and Neck Squamous Carcinoma Cell Line¹

Departments of Medical Oncology [H. K. K., L. A. Z., W. K. H., D. C., L. S., B. S. G.] and Tumor Biology [P. G. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Evidence from several in vitro systems indicates that cellular responses to DNA topoisomerase II-reactive compounds (i.e., the epipodophyllotoxins and intercalating agents) may be affected by the relative rate of proliferation. Using a human head and neck squamous carcinoma cell line 183A, we have investigated the effect of ß-all-trans-retinoic acid (RA), a substance with known antiproliferative effects, on the DNA cleavage and cytotoxic activities of etoposide and 4'-(acridinylamino)methanesulfon-m-anisidide which interact with topoisomerase II. The effect of RA treatment on the activity of X-radiation and bleomycin, both of which produce free radical mediated effects, was also examined. RA treatment (10 to 20 µM for 72 h) does not significantly influence DNA cleavage induced by X-radiation or bleomycin but decreases DNA cleavage and cytotoxicity mediated by etoposide and 4'-(acridinylamino)methanesulfon-m-anisidide. Further, this effect can be demonstrated at a dose of RA that is minimally growth inhibitory. The inhibitory effect of RA appears to be localized to the nucleus given that similar effects on drug-mediated DNA cleavage can be demonstrated in nuclei isolated from RA-treated cells. However, both drug-stimulated DNA cleavage activity and topoisomerase II catalytic activity are approximately equal in crude nuclear extracts of untreated and RA-treated cells. These data suggest that the resistance to topoisomerase II-reactive drugs induced by RA treatment of 183A cells is not mediated through a direct effect on the enzyme, but, instead, is related to other changes in the nuclear milieu occurring in the initial stages of quiescence such as altered chromatin conformation.

¹ This work was supported by a Clinical Oncology Career Development Award (B. S. G.) and Grant CH-324A (L. A. Z.) awarded by the American Cancer Society, USPHS Grants CA 40090 (L. A. Z.) and RR 5511-23 (L. A. Z.), and by a gift to the M. D. Anderson Annual Fund for the Chemotherapy Research Program by Henry C. Beck, Jr., of Dallas, TX (L. A. Z.).

² To whom requests for reprints should be addressed, at Department of Medical Oncology, Box 80, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

Received 12/ 9/87. Revised 3/29/88. Revised 8/16/88. Revised 10/17/88. Accepted 11/30/88.