Mouse skin tumor-initiating activity of 5-, 7-, and 12-methyl- and fluorine-substituted benz[a]anthracenes.

As an approach for elucidation of structure activity relationships that underlie the exceptionally large difference in carcinogenic activity between benz[a]anthracene and 7,12-dimethylbenz[a]anthracene (7,12-DMBA), 11 methyl- and/or fluorine-substituted benz[a]anthracenes were evaluated for tumor-initiating activity on mouse skin. Outbred CD-1 and outbred Sencar mice received a single topical application of the hydrocarbons followed by twice weekly applications of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate for 16-26 weeks. 7,12-DMBA was almost two orders of magnitude more active as a tumor-initiator than 7- and 12-methylbenz[a]anthracene. Methyl substitution at the 7- and 7,12-positions of benz[a]anthracene was significantly more effective in the enhancement of tumorigenic activity than fluorine substitution at these positions. Although 7-fluorobenz[a]anthracene, 12-fluorobenz[a]anthracene, and 7,12-difluorobenz[a]anthracene had only 0.15, 0.26, and less than 0.005 times the tumor-initiating activity of their respective methyl-substituted derivatives, they were severalfold more active than benz[a]anthracene. 7-Fluorobenz[a]anthracene was slightly less active than 12-fluorobenz[a]anthracene, whereas 7-methylbenz[a]anthracene was about twofold more than 12-methylbenz[a]anthracene. For 7,12-di-substituted benz[a]anthracenes, 7-methyl-12-fluorobenz[a]anthracene was more than twice as tumorigenic as 7-fluoro-12-methylbenz[a]anthracene, but each was individually more active than 7-methylbenz[a]anthracene and 12-methylbenz[a]anthracene, respectively. Both fluorinated compounds were much less active than 7,12-DMBA. Substitution of fluorine or methyl at the 5-position of 7-methylbenz[a]anthracene and substitution of fluorine at the 5-position of 12-methylbenz[a]anthracene dramatically reduced their tumorigenic activity.
AuthorsA W Wood, W Levin, R L Chang, A H Conney, T J Slaga, R F O'Malley, M S Newman, D R Buhler, D M Jerina
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 69 Issue 3 Pg. 725-8 (Sep 1982) ISSN: 0027-8874 [Print] UNITED STATES
PMID6810009 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Benz(a)Anthracenes
  • Carcinogens
  • Hydrocarbons, Fluorinated
  • 5-methylbenzanthracene
  • 9,10-Dimethyl-1,2-benzanthracene
  • 12-methylbenzanthracene
  • benz(a)anthracene
  • 7-methylbenzanthracene
  • Tetradecanoylphorbol Acetate
  • 9,10-Dimethyl-1,2-benzanthracene (toxicity)
  • Animals
  • Benz(a)Anthracenes (toxicity)
  • Carcinogens
  • Cocarcinogenesis
  • Female
  • Hydrocarbons, Fluorinated (toxicity)
  • Mice
  • Neoplasms, Experimental (chemically induced)
  • Papilloma (chemically induced)
  • Skin Neoplasms (chemically induced)
  • Structure-Activity Relationship
  • Tetradecanoylphorbol Acetate (toxicity)
  • Time Factors

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