Synthesis and biological evaluation of retinoyl and docosahexaenoyl derivatives of 5-Fluoro-2' -deoxyuridine as anticancer prodrugs

Feng, Liping (2003) Synthesis and biological evaluation of retinoyl and docosahexaenoyl derivatives of 5-Fluoro-2' -deoxyuridine as anticancer prodrugs. Masters thesis, Memorial University of Newfoundland.

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Abstract

According to the survey (Gaudett et a!. 1998, 1996), cancer is the number one disease that causes death in Canada and U.S. Many approaches have been used to treat cancer. Chemotherapy has played and will continue to play an important role in cancer treatment. Although many anticancer drugs are available, there are serious problems associated with cancer chemotherapy including toxicity and development of drug resistance. Retinoids such as all-trans retinoic acid, omega-3 polyunsaturated fatty acids such as cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) and fluoropyrimidines such as 5-fluoro-2'-deoxyuridine (FUdR) have potent distinct anticancer mechanisms. Since many cancer cells are known to overexpress low density lipoprotein (WL) receptors, LDL has been proposed as a cancer specific carrier. In this study, LDL was investigated as a drug carrier to enhance the drug delivery to cancer cells (Hela, MCF7, MB231 and HepG2 cell lines). Four derivatives of FUdR (3' -0-retinoyl-FUdR, 3' -0-docosahexaenoyl-FUdR, 5'- 0-retinoyl-FUdR and 3', 5' -di-0-retinoyl-FUdR) were synthesized as prodrugs of FUdR. The prodrugs were incorporated into LDL. The results showed that the cytotoxicity of the respective prodrugs was increased compared with parent drug FUdR. The prodrug/LDL complex was more effective than the prodrug without LDL as a carrier in Hela cells.

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