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Carcinogenesis, Vol. 22, No. 6, 951-955, June 2001
© 2001 Oxford University Press

CARCINOGENESIS

Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin

Subodh Kumar, Richard L. Chang1,4,, Alexander W. Wood2,, Jian Guo Xie1,, Mou Tuan Huang1,, Xiao Xing Cui1,, Panna L. Kole, Harish C. Sikka, Suresh K. Balani3,, Allan H. Conney1, and Donald M. Jerina3,

Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York, College at Buffalo, Buffalo, NY 14222,
1 Laboratory for Cancer Research, Rutgers, The State University of New Jersey, College of Pharmacy, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020,
2 Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110 and
3 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

CD-1 female mice were initiated with a single topical application of 500 nmol dibenz[a,h]acridine (DB[a,h]Acr), its racemic trans-1,2-, 3,4-, 8,9- and 10,11-dihydrodiols, racemic DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 or racemic DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, where the benzylic hydroxyl group is either cis (isomer 1) or trans (isomer 2) to the epoxide oxygen. The mice were subsequently treated twice weekly with 12-O-tetradecanoylphorbol 13-acetate for 25 weeks. High tumorigenicity was observed only for DB[a,h]Acr, its 10,11-dihydrodiol and DB[a,h]Acr 10,11-diol 8,9-epoxide-2 (3.3, 1.2 and 1.6 tumors/mouse, respectively). The tumor-initiating activity of a 50 nmol dose of DB[a,h]Acr and the optically active (+)- and (–)-enantiomers of DB[a,h]Acr 10,11-dihydrodiol and of the optically active DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2 were also studied. Only DB[a,h]Acr, (–)-DB[a,h]Acr (10R,11R)-dihydrodiol and the bay region (+)-(8R,9S,10S,11R)-diol epoxide-2 were highly active (1.6, 1.7 and 2.4 tumors/mouse, respectively). These results are consistent with previous studies which showed that the corresponding bay region RSSR diol epoxides of benzo[a]pyrene, benz[a]anthracene, chrysene and benzo[c]phenanthrene as well as the aza-polycyclic dibenz[c,h]acridine are the most tumorigenic isomers.


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