Anti-tumor-Promoting activity of tibolone and its metabolites.
The aim of this study was to evaluate the cancer chemopreventive potential of the widely prescribed drug tibolone (17alpha-ethynyl-7alpha-methyl-5(10)-estren-3-one, CAS 5630-53-5) and its main metabolites, 17alpha-ethynyl-7alpha-methyl-4-estren-3-one (CAS 1162-60-3), 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3alpha,17beta-diol (CAS 100239-44-9) and 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3beta,17beta-diol (CAS 100239-45-0), by studying their anti-tumor-promoting activity. To this aim the test compounds were submitted to the short term in vitro assay for the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) as a primary screening for anti-tumor promoters. All the compounds showed high inhibitory activity and low cytotoxicity as compared to literature data. To extend the study to an animal model, tibolone and its 3alpha-hydroxy metabolite (CAS 100239-44-9) were also assayed in the in vivo two-stage on mouse skin carcinogenesis test, exhibiting significant inhibitory effects on TPA promoted mouse skin papillomas formation. A comparison with literature data indicated them as more potent compounds than other steroids previously studied such as digitoxigenin, cortisone, hydrocortisone, and prednisolone.
Colombo
Diego
D
Dipartimento di Chimica, Biochimica e Biotecnologie per la Medicina, Università di Milano, Milan, Italy. diego.colombo@unimi.it
Ferraboschi
Patrizia
P
Franchini
Laura
L
Nishino
Hoyoku
H
Takayasu
Jyunko
J
Tokuda
Harukuni
H
D000818:Animals; D016588:Anticarcinogenic Agents; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D045744:Cell Line, Tumor; D019309:Epstein-Barr Virus Nuclear Antigens / Q000187:drug effects; D005260:Female; D051379:Mice; D009652:Norpregnenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D010212:Papilloma / Q000139:chemically induced / Q000517:prevention & control; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000633:toxicity
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D019309:Epstein-Barr Virus Nuclear Antigens; D009652:Norpregnenes; D020845:Selective Estrogen Receptor Modulators; C027385:tibolone; D013755:Tetradecanoylphorbol Acetate