The primary focus of our study is to investigate the biochemical and molecular changes associated with carcinogen resistance. We developed a series of carcinogen-resistant cells by continuous exposure to BP. These cells are a model for studying the early biochemical and molecular changes which may prevent cancer due to environmental carcinogens and xenobiotics. Our BP resistant cells are also co-resistant to DMBA. To our knowledge this is the first systematic examination of the overall mechanisms involved in carcinogen resistance, including carcinogen efflux, activation, detoxification and DNA repair. Although detoxification enzymes were unchanged, a significant increase in reduced glutathione levels was observed in BP resistant cells.Our observation suggested a redox mediated pathway cascade may be involved in carcinogen resistance. Therefore, we examined the major pathway enzyme of the pentose phosphate shunt, glucose-6-phosphate dehydrogenase (G6PD) and the redox coupling enzyme from the proline cycle, pyrroline 5- carboxylate reductase (P5CR). We found both G6PD and P5CR activities were markedly increased in BP resistant cells compared to WT. We proposed that the major changes in carcinogen resistant cells are in redox mediated DNA repair mechanisms. Our hypothesis was further supported by molecular studies of RNA expression. The expression of G6PD, P5CR, and TOPO II was increased with increasing resistance and HGPRT expression was markedly enhanced at an early stage of resistance but did not increase with further resistance. Whether the redox changes are important in preventing carcinogen initiation in mammary tumors are under our current investigation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC000189-04
Application #
6160852
Study Section
Special Emphasis Panel (LNMR)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Brantley, Eileen; Patel, Vyomesh; Stinson, Sherman F et al. (2005) The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces NF-kappaB activity in drug-sensitive MCF-7 cells. Anticancer Drugs 16:137-43
Dennis, Phillip A; Van Waes, Carter; Gutkind, J Silvio et al. (2005) The biology of tobacco and nicotine: bench to bedside. Cancer Epidemiol Biomarkers Prev 14:764-7
Loaiza-Perez, Andrea I; Kenney, Susan; Boswell, Jamie et al. (2004) Aryl hydrocarbon receptor activation of an antitumor aminoflavone: basis of selective toxicity for MCF-7 breast tumor cells. Mol Cancer Ther 3:715-25
MacDonald, Christopher J; Ciolino, Henry P; Yeh, Grace Chao (2004) The drug salicylamide is an antagonist of the aryl hydrocarbon receptor that inhibits signal transduction induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Res 64:429-34
Ciolino, Henry; MacDonald, Chistopher; Memon, Omar et al. (2003) Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo. Int J Cancer 105:321-5