The hypothesis to be examined is whether tumor promoters induce free radicals or oxidants, whether these oxidants are involved in the mechanism(s) of tumor promotion in mouse epidermis and whether the basis for the known resistance to TPA promotion in C57B1/6 mice as compared to the promotion sensitive SENCAR mouse resides in their differential ability to induce or respond to oxidant production. The rationale for this is based both on literature evidence that antioxidants inhibit promotion while certain organic peroxides have promoting activity and on studies from our laboratory demonstrating that TPA stimulates the production of an oxidant(s) in mouse epidermal cells. We propose to extend these observations through studies designed to answer the following questions, using epidermal cells from SENCAR and C57B1/6 mice treated with TPA, teleocidin, mezerein and A 23187. (1) What is the nature or identity of the tumor promoter-induced oxidant(s)? This will be studied using the following approaches: chemiluminescence, lipid peroxidation, oxygen consumption and electron spin resonance (spin trapping). (2) Do quantitative or qualitative differences exist between the membranes of SENCAR and C57B1/6 mice and is the membrane a target for TPA-induced oxidants? The following parameters will be measured in control and promoter stimulated cells: (a) phospholipid composition and turnover, (b) transmethylation and degradation of methylated phospholipids and (c) identification of the phospholipids that may undergo peroxidation in response to promoters. (3) Can specific radical generating systems mimic known TPA events? The markers to be measured are the induction of ornithine decarboxylase, transglutaminase and DNA synthesis. Additionally, the endogenous antioxidant levels, i.e., basal and promoter-induced levels of superoxide dismutase, catalase and glutathione peroxidase will be compared.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042211-03
Application #
3183178
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-04-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Fischer, S M; Lee, W Y; Locniskar, M F (1995) The pro-inflammatory and hyperplasiogenic action of interleukin-1 alpha in mouse skin. Prog Clin Biol Res 391:161-77
Lee, W Y; Lockniskar, M F; Fischer, S M (1994) Interleukin-1 alpha mediates phorbol ester-induced inflammation and epidermal hyperplasia. FASEB J 8:1081-7
Vo, T K; Fischer, S M; Slaga, T J (1991) Effects of N-acyl dehydroalanines on phorbol ester-elicited tumor development and other events in mouse skin. Cancer Lett 60:25-32
Fischer, S M; Jasheway, D W; Klann, R C et al. (1989) Correlation of phorbol ester promotion in the resistant C57BL/6J mouse with sustained hyperplasia but not ornithine decarboxylase or protein kinase C. Cancer Res 49:6693-9
Fischer, S M; Cameron, G S; Baldwin, J K et al. (1989) The arachidonic acid cascade and multistage carcinogenesis in mouse skin. Prog Clin Biol Res 298:249-64
Fischer, S M; Cameron, G S; Baldwin, J K et al. (1988) Reactive oxygen in the tumor promotion stage of skin carcinogenesis. Lipids 23:592-7
Fischer, S M; Baldwin, J K; Jasheway, D W et al. (1988) Phorbol ester induction of 8-lipoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation but not ornithine decarboxylase induction. Cancer Res 48:658-64
Fischer, S M; Baldwin, J K; Jasheway, D W et al. (1987) Possible dissociation of the phorbol ester-induced oxidant response and tumor promotion in the F1 offspring of SSIN x C57BL/6J mice. Carcinogenesis 8:1521-4
Fischer, S M; Reiners Jr, J J (1986) 7,8-Benzoflavone: an inhibitor of prostaglandin synthesis and ornithine decarboxylase in murine epidermal cultures. Carcinogenesis 7:933-5
Fischer, S M; Baldwin, J K; Adams, L M (1986) Effects of anti-promoters and strain of mouse on tumor promoter-induced oxidants in murine epidermal cells. Carcinogenesis 7:915-8