Date on Master's Thesis/Doctoral Dissertation

8-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Gupta, Ramesh

Author's Keywords

Green tea polyphenols; Lung cancer; Anthocyanidins; Polymeric implant; Benzo[a]pyrene; Neo-adjuvant treatment

Subject

Green tea--Health aspects; Green tea--Therapeutic use; Polyphenols--Physiological effect; Drug delivery systems; Lungs--Cancer--Treatment

Abstract

Green tea polyphenols (GTPs) are gaining increasing attention because of their potential anti-tumor effects. However, poor oral bioavailability limits their efficacy in vivo. In this dissertation, two hypotheses were tested: 1) GTPs administered systemically by a sustained release system will circumvent the problem of limited bioavailability and lower the effective dose compared to the traditional oral route, and 2) adjuvant treatment of GTPs with a standard chemotherapeutic agent (e.g. cisplatin) will enhance efficacy of the therapeutic agent. In our lab, a polymeric implant delivery system was developed, in which GTPs were uniformly embedded within a polycaprolactone matrix to provide sustained release of GTPs. The release profile of GTP implants was further investigated both in vitro and in vivo. To test the first hypothesis, polyphenon E (poly E), a standardized green tea extract, was administered by PCL implants grafted subcutaneously or via the drinking water to SID rats. The animals were challenged by benzo[a]pyrene (BP) via subcutaneous implant. Results showed a significant reduction of BP-induced DNA adducts III the implant group; however, only a modest but insignificant reduction occurred in the drinking water group. Notably, the total dose of poly E administered was > 100-fold lower in the implant group. Analysis of selected phase I, phase II, and DNA repair enzymes at the mRNA, protein levels and enzymatic activity showed no significant modulation by poly E. The effect of poly E on DNA adduct formation was presumably due to scavenging of the reactive intermediates of BP by GTPs, which was illustrated by other experiments in this dissertation. To test the second hypothesis, the combined effects of the GTPs, anthocyanidins and cisplatin on the growth of lung cancer H1299 cells in cell culture and also a xenograft nude mouse model were investigated. In both studies, combination of GTPs-anthocyanidins with cisplatin exerted a more dramatic anti-cancer effect. However, systemic toxicity was found in the animals receiving the combination treatment. Possible mechanism of action was investigated. Together, these data demonstrated that sustained systemic delivery of poly E lower the effective dose by overcoming oral bioavailability and combination of GTPs-anthocyanidins and suboptimal doses of cisplatin may be effective in neo-adjuvant chemotherapy.

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