Tumorigenicity of four optically active bay-region 3,4-diol 1,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h]acridine on mouse skin and in newborn mice

Citation
Rl. Chang et al., Tumorigenicity of four optically active bay-region 3,4-diol 1,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h]acridine on mouse skin and in newborn mice, CARCINOGENE, 21(11), 2000, pp. 1997-2003
Citations number
48
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
CARCINOGENESIS
ISSN journal
01433334 → ACNP
Volume
21
Issue
11
Year of publication
2000
Pages
1997 - 2003
Database
ISI
SICI code
0143-3334(200011)21:11<1997:TOFOAB>2.0.ZU;2-O
Abstract
The nitrogen heterocycle dibenz[c,h]acridine (DB[c,h]ACR) and the enantiome rs of the diastereomeric pair of bay-region 3,4-diol 1,2-epoxides as well a s other bay-region epoxides and dihydrodiol derivatives of this hydrocarbon have been evaluated for tumorigenicity on mouse skin and in the newborn mo use. On mouse skin, a single topical application of 50 or 200 nmol of compo und was followed 10 days later by twice-weekly applications of the tumor pr omoter 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. DB[c,h]ACR and th e four optically pure, bay-region 3,4-diol-1,2-epoxide isomers all had sign ificant tumor-initiating activity, The isomer with (1R,2S,3S,4R) absolute c onfiguration [(+)-DE-2] was the most active diol epoxide isomer, The (-)-(3 R,3R)-dihydrodiol of DB[c,h]ACR, the expected metabolic precursor of the ba y-region (+)-DE-2, was 4- to 6-fold more tumorigenic than its corresponding (+)-enantiomer, In tumorigenicity studies in newborn mice, a total dose of 70-175 nmol of DB[c,h]ACR or one of its derivatives was Injected i,p, on d ays 1, 8 and 15 of life, and tumorigenic activity was determined when the m ice were 36-39 weeks old. DB[c,h]ACR produced a significant number of pulmo nary tumors and also produced hepatic tumors in male mice. Of the four opti cally active bayregion diol epoxides, only (+)-DE-2 and (+)-DE-1 with (1R,2 S,3S,4R) and (1S,2R,3S,4R) absolute configuration, respectively, produced a significant tumor incidence. At an equivalent dose, the (+)-DE-2 isomer pr oduced severalfold more pulmonary tumors and hepatic tumors than the (+)-DE -1 isomer, The (-)-(3R,4R)-dihydrodiol, metabolic precursor of the bay-regi on (+)-DE-2, was strongly active and induced an equal number of pulmonary a nd hepatic tumors as did DB[c,lt]ACR. The (+)-(35,4S) dihydrodiol was less active. The bay-region (+)-(1R,2S)-epoxide of 1,2,3,4-tetrahydro DB[c,h]ACR was strongly tumorigenic in newborn mice whereas its (-)-(1S,2R)-enantiome r was inactive. This contrasts with the data on mouse skin where both enant iomers had substantial tumorigenic activity. In summary, the bay-region (+) -(1R,2S,3S,4R)-3,4-diol 1,2-epoxide of DB[c,h]ACR was the most tumorigenic of the four optically active bay-region diol epoxides of DB[c,h]ACR on mous e skin and in the newborn mouse, These results with a nitrogen heterocycle are similar to earlier data indicating high tumorigenic activity for the R, S,S,R bay-region diol epoxides of several carbocyclic polycyclic aromatic h ydrocarbons.