7,12-Dimethylbenz[a]anthracene

About: 7,12-Dimethylbenz[a]anthracene is a research topic. Over the lifetime, 1717 publications have been published within this topic receiving 40892 citations.

Two-Stage Tumorigenesis of Dermal Melanocytes in the Back Skin of the Syrian Golden Hamster Using Systemic Initiation with 7, 12-Dimethylbenz(a)anthracene and Topical Promotion with 12-O-Tetradecanoylphorbol-13-acetate

Abstract: Tumor formation in terms of a two-stage mechanism after initiation with 7,12-dimethylbenz(a)anthracene (DMBA) and promotion with 12- O -tetradecanoylphorbol-13-acetate (TPA) has been investigated in the Syrian golden hamster. Forty hamsters were initiated intragastrically by two applications of DMBA (50 mg/kg body weight each), followed by repeated topical promotion with 20 nmol TPA. In comparison with the corresponding control groups (no treatment, DMBA initiation only, and TPA treatment only), a clear-cut two stage mechanism was observed to operate in the perifollicular dermal melanocytes, leading to the early appearance of a high incidence of benign melanomas. Upon transplantation to normal hosts, these tumors rapidly underwent malignant growth and developed pigmented metastases in several organs. The morphology of melanoma formation resembled that described for DMBA-mediated melanocytic carcinogenesis in hamsters. The effect of TPA alone consisted of both a reactivation of nonfunctional melanocytes and an enhanced proliferation of the perifollicular melanocytic population. Thus, like epithelial two-stage carcinogenesis, pigmentary cell tumor promotion seems to be linked to a hyperplasia of the target cell under consideration. Although evidence for two-stage carcinogenesis also exists for some internal organs ( i.e. , esophagus, forestomach, liver), the dorsal epidermis did not show morphological alterations worth mentioning, despite the relatively high amounts of TPA applied. Even epidermal hyperplasia, normally the consequence of TPA application to mammalian skin, could scarcely be observed. Consistent with the view of an interdependence of hyperplastic and promoting capacity of phorbol esters, no tumors developed in the dorsal epidermis. In accordance with recent findings on two-stage carcinogenesis mechanisms in various organs of different animal species, melanocytic two-stage carcinogenesis in the hamster not only strengthens the general validity of the principle but also provides an excellent model for the study of melanotic tumors closely resembling those of humans.

Mutagenicity and Tumor-initiating Activity of Fluorinated Derivatives of 7,12-Dimethylbenz(a)anthracene

Abstract: 7,12-Dimethylbenz(a)anthracene (DMBA) and its 1-, 2-, 5-, and 11-fluoro derivatives were tested to determine their mutagenicity for ouabain resistance in Chinese hamster V79 cells and their tumor-initiating activity in mouse skin. Inasmuch as V79 cells do not metabolize polycyclic aromatic hydrocarbons, mutagenesis was tested both in the presence and in the absence of golden hamster embryo cells capable of metabolizing polycyclic aromatic hydrocarbons. Neither DMBA nor any of the fluorinated derivatives showed mutagenicity for V79 cells in the absence of the golden hamster cells. In the presence of these cells, DMBA and 11-fluoro-DMBA exhibited a comparable mutagenic response that was dose dependent. At a dose as low as 0.01 ..mu..m, a 7- to 10-fold increase in the frequency of ouabain-resistant mutants was observed. The other derivatives were either inactive or required more than a 1000-fold higher dose to induce a comparable mutagenic response. Similarly, both DMBA and 11-fluoro-DMBA at 100 nmol initiated tumors in 100% of the tested mice, whereas the other fluorinated derivatives at this dose initiated skin tumors in 15% or less of the treated mice. The average number of papillomas per mouse induced by 1-, 2-, and 5-fluoro-DMBA was more than 100-fold lower than the number inducedmore » by DMBA or 11-fluoro-DMBA. These results suggest that carbon positions 1 and 2 of DMBA, which are located at the bay region, and position 5, which is located at the K-region, are involved in the metabolic activation of DMBA into mutagenic and carcinogenic metabolites.« less

Mutational spectra in the lacl gene in skin from 7,12-dimethylbenz[a]anthracene-treated and untreated transgenic mice.

Abstract: Transgenic mice carrying the bacterial lacl gene in a lambda shuttle vector were used to isolate and characterize background and 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutations in skin Adult male mice were treated once topically with either DMBA or acetone or were left untreated Seven days later, DMBA treatment had significantly increased the mutant frequency in the skin (mean +/- SEM, 36 +/- 3 x 10(-5)) versus in vehicle-treated (64 +/- 12 x 10(-5)) and untreated mice (71 x 10 x 10(-5)) At least 10 mutants from each of three DMBA-treated and three untreated mice were selected for DNA sequence analysis In each case, the entire 1080-bp target gene was sequenced Base-pair substitutions predominated (86 of 96 mutations), although frameshift and deletion mutations were also detected Twelve percent of the mutants carried more than one mutation In controls, the mutations were predominantly GC-->AT transitions (26 of 42), and no AT-->TA transversions were recovered In contrast, in the DMBA-treated mice, AT-->TA transversions represented 42% of the mutations (23 of 54) and GC-->AT transitions accounted for only 11% The AT-->TA transversions occurred mostly at 5'-CA sites This class of mutation has been recovered frequently in ras genes from DMBA-treated mice and probably represents an early event in carcinogenesis (Nelson MA et al, Proc Natl Acad Sci USA 89:6398-6402, 1992) Our present results are consistent with the types of DNA damage induced by DMBA The observation of different mutant frequencies and spectra in treated and control mice demonstrates the utility of this approach in the study of mutagenesis in vivo