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Modulation by Adriamycin, Daunomycin, Verapamil, and Trifluoperazine of the Biochemical Processes Linked to Mouse Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-acetate¹

Anti-Cancer Drug Laboratory, Division of Biology, Kansas State University, Ackert Hall, Manhattan, Kansas 66506

The antitumor antibiotics Adriamycin (ADR) and daunomycin (DAU) were tested for their ability to alter some of the molecular events linked to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). When applied topically to mouse skin, DAU is a more effective inhibitor of the basal level of epidermal DNA synthesis than ADR. However, these drugs alone are unable to inhibit the sequential induction of RNA, protein, and DNA synthesis caused by TPA in mouse epidermis in vivo. Moreover, ADR enhances substantially the induction of epidermal ornithine decarboxylase (ODC) activity by TPA.

In vitro, the incorporation of [³H]DAU into isolated epidermal cells resembles more that of the HL-60 cells resistant to vincristine than that of the parental cell line. TPA does not alter the incorporation of [³H]DAU into epidermal cells. The Ca²⁺ antagonists verapamil (VRP) and trifluoperazine (TFP) enhance significantly the amount of [³H]DAU associated with the epidermal cells after 1 h.

When applied shortly before TPA in vivo, VRP and TFP inhibit TPA-induced ODC activity at 5 h and TPA-induced DNA synthesis at 17 h. Moreover, the combinations of Ca²⁺ antagonists and anthracycline antibiotics administered before TPA inhibit synergistically these ODC and DNA responses to the tumor promoter. When they are applied at various times after TPA treatment, the same combinations of ADR or DAU and VRP or TFP fail to alter TPA-induced RNA and protein synthesis but still exert synergistic inhibitory effects on the peak of DNA synthesis observed 17 h after TPA. However, the chronic administration of ADR and DAU alone or in combination with VRP prior to the peak of TPA-induced DNA synthesis 16 h after each promotion treatment with TPA fails to alter the promotion of skin papillomas in the two-stage protocol of mouse skin carcinogenesis. In contrast, when administered alone or in combination with DAU prior to each TPA treatment, VRP inhibits skin tumor promotion and reveals the antitumor-promoting activity of DAU.

These results point to the modulatory role of Ca²⁺ in the action of ADR and TPA and demonstrate the refractory nature of mouse epidermis to cancer chemotherapy by anthracycline antibiotics. However, ADR and DAU may be effective against skin tumor promotion if they are applied in combination with Ca²⁺ antagonists and at a time when they can inhibit the inductions of both ODC activity and DNA synthesis by TPA.

¹ This investigation was supported by the American Cancer Society (Grant BC-600), NIH Grant CA-40083 awarded by the National Cancer Institute, Department of Health and Human Services, the Wesley Foundation of Wichita (Wesley Scholar Program: Molecular Biology and Cell Growth Regulation) and the Center for Basic Cancer Research, Kansas State University. A preliminary report of this work was presented at the Eightieth Annual Meeting of the American Association for Cancer Research, May 1989, San Francisco, CA (1).

² To whom requests for reprints should be addressed.

Received 10/28/88. Revised 4/ 7/89. Revised 6/23/89. Accepted 7/ 5/89.

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