Epidemiological studies suggest an inverse correlation between soyfood consumption and human cancer mortality. Laboratory studies indicate that soy diets also inhibit experimentally induced animal tumors. Although most studies attribute the anticarcinogenic effect of soybeans to the protease inhibitors, increasing evidence suggests that isoflavones, non- protein components richly present in soybeans, may also play important roles. Genistein, one of the major soybean isoflavones, has been shown to inhibit tyrosine protein kinase (TPK), DNA topoisomerase II (Topo II), and ribosomal S6 kinase (RS6K), suppress tumor cell growth, and induce differentiation of several malignant cell lines. Our preliminary studies have shown that genistein significantly prevents 7,12- dimethylbenz[a]anthracene (DMBA)-DNA adduct formation and inhibits 12-O- tetradecanoyl phorbol-13-acetate (TPA)-induced H2O2 formation, inflammatory responses, and proto-oncogene expression in vivo. However, whether genistein modifies chemical carcinogenesis in vivo remains unclear. This proposal is designed to test the hypothesis that genistein inhibits oxidative DNA damage induced by carcinogenic agents and further modifies the initiational, promotional, and progressional processes of chemical carcinogenesis. The overall objective is to determine if genistein modifies the initiation- and promotion-related events and subsequently inhibits skin tumor formation in vivo. The initial aim of the project is to determine if topical application of genistein modifies the initiation- and promotion-related events with an emphasis on oxidative DNA damage.
The second aim i s to determine if topical application of genistein affects initiation, promotion and/or progression of multistage skin. carcinogenesis.
The third aim i s to examine if topical application of genistein inhibits the DMBA-induced complete carcinogenesis. Finally, we will determine if dietary administration of genistein modulates these carcinogenic processes in the multistage carcinogenesis model. If, in fact, genistein has anticarcinogenic effects, an elucidation of the mechanisms of genistein's action will contribute to application of this soybean isoflavone in prevention and/or therapy of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA060994-03
Application #
2101756
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1993-08-18
Project End
1996-06-30
Budget Start
1995-08-31
Budget End
1996-06-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Wang, Y; Rosenstein, B; Goldwyn, S et al. (1998) Differential regulation of P53 and Bcl-2 expression by ultraviolet A and B. J Invest Dermatol 111:380-4
Wang, Y; Zhang, X; Lebwohl, M et al. (1998) Inhibition of ultraviolet B (UVB)-induced c-fos and c-jun expression in vivo by a tyrosine kinase inhibitor genistein. Carcinogenesis 19:649-54
Brown, A; Jolly, P; Wei, H (1998) Genistein modulates neuroblastoma cell proliferation and differentiation through induction of apoptosis and regulation of tyrosine kinase activity and N-myc expression. Carcinogenesis 19:991-7
Wei, H; Bowen, R; Zhang, X et al. (1998) Isoflavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice. Carcinogenesis 19:1509-14
Wei, H; Ca, Q; Rahn, R et al. (1998) DNA structural integrity and base composition affect ultraviolet light-induced oxidative DNA damage. Biochemistry 37:6485-90
Wei, H; Cai, Q; Tian, L et al. (1998) Tamoxifen reduces endogenous and UV light-induced oxidative damage to DNA, lipid and protein in vitro and in vivo. Carcinogenesis 19:1013-8
Zhang, X; Rosenstein, B S; Wang, Y et al. (1997) Induction of 8-oxo-7,8-dihydro-2'-deoxyguanosine by ultraviolet radiation in calf thymus DNA and HeLa cells. Photochem Photobiol 65:119-24
Giles, D; Wei, H (1997) Effect of structurally related flavones/isoflavones on hydrogen peroxide production and oxidative DNA damage in phorbol ester-stimulated HL-60 cells. Nutr Cancer 29:77-82
Wei, H; Cai, Q; Rahn, R et al. (1997) Singlet oxygen involvement in ultraviolet (254 nm) radiation-induced formation of 8-hydroxy-deoxyguanosine in DNA. Free Radic Biol Med 23:148-54
Zhang, X; Rosenstein, B S; Wang, Y et al. (1997) Identification of possible reactive oxygen species involved in ultraviolet radiation-induced oxidative DNA damage. Free Radic Biol Med 23:980-5

Showing the most recent 10 out of 17 publications