Vipra Kundoor

Document Type

Thesis - University Access Only

Award Date

2006

Degree Name

Master of Science (MS)

Department / School

Pharmaceutical Sciences

Abstract

Sarcophine derivatives have been suggested to be chemopreventive in nature. One of its derivative, sarcophine-triol (ST), was investigated to study the skin cancer chemopreventive effects in chemically and DVB-induced carcinogenesis in female CD-1 and SKH-1 mice respectively. For chemically induced carcinogenesis, three groups (control, promotion, initiation) of 30 female CD-1 mice each were taken. Carcinogenesis was initiated with 7, 12-dimethylbenz (a) anthracene (DMBA) and promoted with 12-Otetradecanoylphorbol-13-acetate(TPA). One hour before treating with DMBA (200 nrnol/100 μl acetone), control and promotion groups were treated with acetone (100 μI) and initiation group with ST (30 μg/100 μl of acetone). Beginning one week after initiation with DMBA, control and initiation groups were treated with acetone and promotion group with ST (30 μg/100 μl of acetone), one hour before treating with TPA (5 nmol/100 μl acetone). This was carried out twice a week for the next 20 weeks. Group weights and tumor counts were taken once every week. The effects of ST on 3Hthymidine incorporation in epidermal DNA, the possible role of apoptotic proteins and COX-2 involved in the prevention of skin tumor development of CD-1 mice were investigated. For DVB-induced carcinogenesis, both a long term as well as a short term experiment was carried out to investigate the chemopreventive effects of ST in chronic as well as sub-chronic conditions respectively. For the long term experiment 54 female SKH-1 mice were divided into two groups, control and ST treated. Both initiation and promotion was induced by UVB radiation (180 mJ/cm2 for lmin.20sec). During the initiation phase control was treated with acetone (100 μl) and ST treated with ST (30 μg/100 μl of acetone) one hour before treating with UVB (180 mJ/cm2 for lmin.20sec). This was carried out every day for two weeks, and 10 days after the initiation phase promotion phase was started. During the promotion phase, control and ST treated were treate d in the same way as they were treated during the initiation phase, but they were treated only twice a week and this treatment was continued for the next 30 weeks. Group weights and tumor counts were taken once every week. A short term experiment was carried out by taking 6 female CD-1 mice. Mice were categorized and treated in the same way as they were in the long term experiment. This treatment was carried out for only 1 week. The role of apoptotic proteins and tumor suppressor genes in the chemopreventive activity of ST were investigated. For the chemically induced carcinogenesis, tumor incidence and multiplicity was found to be 100%, 73%, 96% and 8.2, 4. 8, 9.7 in control, promotion and initiation groups respectively. ST treatme nt resulted in a significant (P ::; 0. 05) inhibition in the incorporation of 3H-thymidine in epidermal DNA in the chemically induced carcinogenesis. The promotion group showed significantly (P::; 0.05) higher levels of caspase-3, -8, -9 and lower levels of COX-2 compared to the control. No significant difference in caspase-3, -8, -9 and COX-2 levels were observed in the initiation group with respect to control. For the UVB long term experiment, tumor incidence and multiplicity was found to be 100%, 92% and 19.6, 5.2 in the control and ST treated groups respectively. Caspase-3, -8, -9 and p53 were significantly (P 􀃈 0. 05) upregulated in ST treated compared to control in both long term as well as in short term experiment. Together, this study for the first time identifies the chemopreventive effects of ST in chemically and UVB induced carcinogenesis and elucidates the mechanism possibly by inducing apoptosis, upregulating p53 protein and decreasing the COX-2 levels, contributing to its overall cancer chemopreventive effects in the mouse skin cancer model.

Library of Congress Subject Headings

Skin -- Cancer -- Chemoprevention

Skin -- Cancer -- Animal models

Format

application/pdf

Number of Pages

76

Publisher

South Dakota State University

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