Anti-tumor promoting action of phthalic acid mono-n-butyl ester cupric salt, a biomimetic superoxide dismutase.
Skin tumor promotion induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was inhibited by a concurrent and topical application of phthalic acid mono-n-butyl ester cupric salt (PAMBCu) in CD-1 mice initiated with 7,12-dimethylbenz[a]anthracene. PAMBCu inhibited TPA-caused epidermal ornithine decarboxylase (ODC) induction and ear edema formation, i.e. skin inflammation. However, neither PAMBCu nor superoxide dismutase (SOD) inhibited TPA-caused ODC induction in primary cultured mouse epidermal cells. 7-Bromomethylbenz[a]anthracene (BrMBA) is known to be a non-TPA type of tumor promoting agent. Epidermal ODC induction and inflammation caused by BrMBA were not inhibited by a concurrent application of PAMBCu. When mice were topically treated twice with PAMBCu, i.e. concurrently with and 7 h after BrMBA treatment, BrMBA-caused ODC induction was markedly suppressed. The same dose regimen of PAMBCu, however, failed to inhibit tumor promotion and inflammation caused by BrMBA. PAMBCu showed SOD-mimetic activity in superoxide generating systems, i.e. xanthine-xanthine oxidase reaction and TPA-stimulated polymorphonuclear leukocytes (PMN). Mono-n-butyl phthalate, which lacks SOD-mimetic activity, failed to inhibit TPA-caused ODC induction and skin inflammation. Therefore, inhibition by PAMBCu of TPA-caused tumor promotion, epidermal ODC induction and inflammation may be attributable to its SOD-mimetic activity. The results also support the contention that a superoxide anion of non-epidermal cell origin, such as PMN and macrophages, plays a role (probably some enhancing role) in in vivo ODC induction and tumor promotion caused by TPA. Failure of PAMBCu to inhibit BrMBA-caused tumor promotion suggests that superoxide anion generation is not involved in the tumor promoting action of this agent and that the anti-tumor promoting action of PAMBCu is dependent on the nature of the tumor promoting agents.
Yamamoto
S
S
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Nakadate
T
T
Aizu
E
E
Kato
R
R
D015127:9,10-Dimethyl-1,2-benzanthracene; D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001551:Benz(a)Anthracenes / Q000009:adverse effects; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000209:etiology; D003993:Dibutyl Phthalate / Q000494:pharmacology*; D004427:Ear Diseases / Q000139:chemically induced; D004487:Edema / Q000139:chemically induced; D004790:Enzyme Induction; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects; D005260:Female; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010212:Papilloma / Q000139:chemically induced; D010795:Phthalic Acids / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced; D013482:Superoxide Dismutase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage
D000970:Antineoplastic Agents; D001551:Benz(a)Anthracenes; D010795:Phthalic Acids; D003993:Dibutyl Phthalate; C001903:7-bromomethylbenzanthracene; D015127:9,10-Dimethyl-1,2-benzanthracene; D013482:Superoxide Dismutase; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate