Satyamoorthy K, Perchellet J P
Division of Biology, Kansas State University, Manhattan 66506.
Cancer Res. 1989 Oct 1;49(19):5364-70.
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.
对抗肿瘤抗生素阿霉素（ADR）和柔红霉素（DAU）进行了测试，以考察它们改变一些与12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）诱导皮肤肿瘤相关分子事件的能力。当局部应用于小鼠皮肤时，DAU对表皮DNA合成基础水平的抑制作用比ADR更有效。然而，单独使用这些药物无法抑制TPA在体内小鼠表皮中依次诱导的RNA、蛋白质和DNA合成。此外，ADR显著增强了TPA对表皮鸟氨酸脱羧酶（ODC）活性的诱导作用。在体外，[3H]DAU掺入分离的表皮细胞的情况，与对长春新碱耐药的HL - 60细胞更相似，而与亲代细胞系不同。TPA不改变[3H]DAU掺入表皮细胞的情况。钙离子拮抗剂维拉帕米（VRP）和三氟拉嗪（TFP）在1小时后显著增加了与表皮细胞结合的[3H]DAU的量。在体内TPA给药前不久应用时，VRP和TFP在5小时抑制TPA诱导的ODC活性，在17小时抑制TPA诱导的DNA合成。此外，在TPA之前给予钙离子拮抗剂和蒽环类抗生素的组合，可协同抑制这些对肿瘤启动子的ODC和DNA反应。当在TPA处理后的不同时间应用时，ADR或DAU与VRP或TFP的相同组合不能改变TPA诱导的RNA和蛋白质合成，但仍对TPA后17小时观察到的DNA合成峰值发挥协同抑制作用。然而，在每次用TPA进行促癌处理后16小时，在TPA诱导的DNA合成峰值之前单独或与VRP联合长期给予ADR和DAU，未能改变小鼠皮肤致癌两阶段方案中皮肤乳头状瘤的促癌作用。相反，当在每次TPA处理前单独或与DAU联合给予VRP时，VRP可抑制皮肤肿瘤的促癌作用，并揭示了DAU的抗肿瘤促癌活性。这些结果表明钙离子在ADR和TPA作用中的调节作用，并证明了小鼠表皮对蒽环类抗生素癌症化疗的难治性。然而，如果ADR和DAU与钙离子拮抗剂联合应用，并在它们能够抑制TPA诱导的ODC活性和DNA合成诱导作用的时间应用，则可能对皮肤肿瘤的促癌作用有效。
