Date of Award

2009

Degree Type

Thesis

Degree Name

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. James Koropatnickcancer, antisense, thymidylate synthase, indoleamine 2,3 dioxygenase, siRNA, RNAi, drug resistance, chemotherapy, immune tolerance, combined therapy

Abstract

Combining therapeutic agents, as a cancer treatment strategy, using antisense targeting thym idylate synthase (TS) and indoleam ine 2,3-dioxygenase (IDO) can potentially reduce tumour cell proliferation, enhance TS-targeting chemosensitivity and enhance tumour immune recognition. However, it must be determined if one reagent modifies the effectiveness of another. The effects of combining small-interfering RNA (siRNA) targeting TS and IDO on target mRNA levels and sensitivity to TS-targeting and other drugs were investigated. IDO or TS siRNA alone reduced their mRNA targets specifically and without effects on non-target mRNAs. IDO siRNA combined with TS siRNA did not affect TS siRNA knockdown of TS mRNA. TS siRNA, however, reduced the ability of IDO siRNA to down-regulate IDO mRNA. IDO siRNA did not affect TS siRNA- induced specific drug sensitivity. Targeting multiple mRNAs simultaneously may not have the effect predicted by studies involving single siRNAs. These results are

important in determining potential drug combinations in anticancer therapy.

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