Satyamoorthy K, Perchellet J P
Kansas State University, Division of Biology, Manhattan 66506.
Cancer Lett. 1990 Dec 3;55(2):135-42. doi: 10.1016/0304-3835(90)90023-q.
The anti-cancer drugs Adriamycin (ADR) and Daunomycin (DAU) alone were unable to inhibit the promotion of skin papillomas by repeated applications of 8.5 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mice. Pretreatments with 50 micrograms of ADR also failed to alter the tumor-promoting activities of smaller doses of TPA. Therefore, the effects of the anthracycline antibiotics on skin tumor promotion were evaluated in combination with the Ca2+ antagonist verapamil (VRP) and the protein kinase C (PKC) inhibitor palmitoylcarnitine (PC), compounds known to circumvent drug resistance. When applied simultaneously with each promotion treatment with 8.5 nmol of TPA, 2.5 mg of VRP inhibited the number of papillomas/mouse by 26%. But the combination of VRP + 50 micrograms of ADR or DAU inhibited the yields of papillomas by 50 or 47%, respectively, suggesting that VRP was required to reveal the antitumor-promoting activities of otherwise ineffective drugs. Similarly, the promotion of skin tumors by TPA was inhibited synergistically by the combinations of 2 mumol of PC + 50 micrograms of ADR or DAU. For instance, ADR and DAU had no effects alone but inhibited the incidence of skin papillomas by 78 and 86%, respectively, in the presence of PC, a compound which alone inhibited the tumor incidence by only 44%. The results indicate that ADR and DAU are effective against the promoting component of skin carcinogenesis only if they are applied in combination with Ca2+ antagonists or PKC inhibitors at a time when they can inhibit the early biochemical effects induced by TPA.
单独使用抗癌药物阿霉素（ADR）和柔红霉素（DAU）无法抑制在经7,12-二甲基苯并(a)蒽（DMBA）启动的小鼠中，通过重复涂抹8.5 nmol的12-O-十四烷酰佛波醇-13-乙酸酯（TPA）所促进的皮肤乳头瘤的生长。用50微克ADR进行预处理也未能改变较小剂量TPA的促肿瘤活性。因此，结合已知可规避耐药性的钙离子拮抗剂维拉帕米（VRP）和蛋白激酶C（PKC）抑制剂棕榈酰肉碱（PC），评估了蒽环类抗生素对皮肤肿瘤促进作用的影响。当与每次8.5 nmol TPA的促癌处理同时应用时，2.5 mg VRP可使每只小鼠的乳头瘤数量减少26%。但VRP + 50微克ADR或DAU的组合分别使乳头瘤的产量减少了50%或47%，这表明需要VRP来揭示原本无效药物的抗肿瘤促进活性。同样，2 μmol PC + 50微克ADR或DAU的组合可协同抑制TPA对皮肤肿瘤的促进作用。例如，ADR和DAU单独使用时没有效果，但在PC存在的情况下，分别使皮肤乳头瘤的发生率降低了78%和86%，而PC单独使用时仅使肿瘤发生率降低44%。结果表明，只有当ADR和DAU与钙离子拮抗剂或PKC抑制剂联合应用，且能抑制TPA诱导的早期生化效应时，它们才对皮肤致癌作用的促进成分有效。
