Inhibition of mouse skin tumor promotion by adriamycin and daunomycin in combination with verapamil or palmitoylcarnitine.
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.
Satyamoorthy
K
K
Kansas State University, Division of Biology, Manhattan 66506.
Perchellet
J P
JP
D000818:Animals; D003630:Daunorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D005260:Female; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D010172:Palmitoylcarnitine / Q000008:administration & dosage / Q000627:therapeutic use*; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
D010172:Palmitoylcarnitine; D004317:Doxorubicin; D014700:Verapamil; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D003630:Daunorubicin