alexa Dual-acting 5-Fluorodeoxyuridine (FUdR) Prodrugs: Cell Death Induced by 3 ’ - O -retinoyl-5-fluoro-2 ’ -deoxyuridine and 5 ’ - O -[bis(2,2,2,-trichloroethyl) phosphoryl-3 ’ - O -butanoyl]-5-fluoro-2 ’ -deoxyuridine | Abstract
ISSN: 2161-1459

Journal of Clinical & Experimental Pharmacology
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Research Article

Dual-acting 5-Fluorodeoxyuridine (FUdR) Prodrugs: Cell Death Induced by 3 ’ - O -retinoyl-5-fluoro-2 ’ -deoxyuridine and 5 ’ - O -[bis(2,2,2,-trichloroethyl) phosphoryl-3 ’ - O -butanoyl]-5-fluoro-2 ’ -deoxyuridine

Zuping Xia1, Edward E Knaus2 and Leonard I Wiebe3*

1College of Pharmacy, Washington State University, Spokane, USA

2Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada

3Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

*Corresponding Author:
Leonard I Wiebe
Oncological Imaging
1807 Cross Cancer Institute, Edmonton
Canada T6G 1Z2
Tel: +1780-432-8524
Fax: +1780-435-0636
E-mail: [email protected]

Received date: October 16, 2013; Accepted date: December 05, 2013; Published date: December 15, 2013

Citation: Xia Z, Knaus EE, Wiebe LI (2013) Dual-acting 5-Fluorodeoxyuridine (FUdR) Prodrugs: Cell Death Induced by 3’-O-retinoyl-5-fluoro-2’-deoxyuridine and 5’-O-[bis(2,2,2,-trichloroethyl)phosphoryl-3’-O-butanoyl]-5-fluoro-2’-deoxyuridine. Clin Exp Pharmacol 3:143. doi:10.4172/2161-1459-3-143

Copyright: © 2013 Xia Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Several novel 5-fluoro-2’-deoxyuridine (FUdR) prodrugs with postulated dual mechanisms of anticancer activity based on nucleoside cytotoxicity and cell differentiation induced by retinoic acid/butyric acid have been reported. The O-retinoyl- and O-butanoyl- esters of FUdR were reported to be more potent and had broader anticancer spectra than either FUdR or 5-fluorouracil (FU) against a bank of human cancer cell lines. The induction of necrosis or apoptosis in HL-60 cells by 3’-O-retinoyl-5-fluoro-2’-deoxyuridine (RFUdR) and the masked butyryl ester nucleotide, 5’-O-bis(trichloroethyl)phosphoryl-3’-O-butanoyl-5-fluoro-2’-deoxyuridine (BTCEP-BFUdR), is now reported. Apoptosis was the major pathway of HL-60 cell death caused by RFUdR (1 × 10-5 M), independent of the exposure time. In contrast, apoptosis and necrosis were equally evident after exposure to BTCEP-BFUdR (1 × 10-5 M) for 48 h, which is similar to the effect of FUdR. These in vitro data support a cytotoxicity model in which release of the nucleoside (FUdR) and the cell differentiator (all-trans retinoic acid, RA or butyrate, NaBu) from the respective prodrugs act synergistically to induce greater cell killing.

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