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Verapamil-mediated Sensitization of Doxorubicin-selected Pleiotropic Resistance in Human Sarcoma Cells: Selectivity for Drugs Which Produce DNA Scission¹

Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

The effects of verapamil on the cytotoxicity and accumulation of multiple drugs were studied in a model of pleiotropic resistance generated by doxorubicin (DOX) selection of the human sarcoma cell line MES-SA. The in vitro sensitivity of the DOX-resistant variant (named Dx5), which is 50- to 100-fold resistant to DOX compared to MES-SA, was enhanced approximately 7-fold by verapamil (3 µg/ml). In addition, the cytotoxicity of several agents to which the Dx5 line displays cross-resistance, i.e., daunorubicin, dactinomycin, mitoxantrone, and etoposide, was also enhanced 2- to 14-fold by verapamil. These agents share the properties of DNA intercalation and/or interaction with topoisomerase II. In contrast, verapamil did not alter the sensitivity of Dx5 to several other agents to which cross-resistance had been demonstrated, i.e., vincristine, vinblastine, colchicine, mitomycin C, and melphalan; nor did verapamil enhance the cytotoxicity of DOX or other agents against the DOX-sensitive parent, MES-SA.

The sensitizing effect of verapamil did not correlate well with its effects on intracellular drug accumulation. [¹⁴C]DPX accumulation was increased by 30–40% in Dx5 but not in MES-SA cells in the presence of verapamil. [³H]Vinblastine accumulation was increased by 24–72% in both MES-SA and Dx5 cells in the presence of verapamil, although cytotoxicity of the Vinca alkaloids was not affected.

In this human sarcoma model of DOX-selected pleiotropic resistance, verapamil partially reversed the resistance to DOX, as well as four of the nine drugs for which cross-resistance had been demonstrated in Dx5. The potentiation by verapamil of the cytotoxicity of some but not all of these antitumor agents suggests that factors other than altered drug transport may be responsible. The pattern of sensitization, restricted to agents which produce DNA strand scission by interaction with topoisomerase II, suggests that verapamil may be acting to promote the formation or inhibit the repair of such DNA strand breaks.

¹ Supported by NIH Grant CA 33303, RCDA-CA-0777 (R.A.N.) and American Cancer Society Grant CH-323. A preliminary report has been presented at the 1984 meeting of the American Association for Cancer Research, Toronto, Canada.

² Present address: Medical Oncology 111C, VA Medical Center, 500 Foothill Dr., Salt Lake City, UT 84148. Dr. Harker was supported by an Institutional National Research SErvice Award in Clinical Pharmacology, USPHS GM-07065.

³ Present address: Department of Chemotherapy Research, M.D. Anderson Hospital and Tumor Institute, Houston, TX 77030.

⁴ To whom requests for reprints should be addressed at, Oncology Division, Room M-211, Department of Medicine, Stanford University Medical Center, Stanford, CA 94305. Dr. Sikic is a recipient of a faculty development award in clinical pharmacology from the Pharmaceutical Manufacturers Association Foundation.

Received 7/29/85. Revised 12/31/85. Accepted 1/31/86.

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