Journal of Clinical & Experimental Pharmacology

Abstract

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 Xia, Edward E Knaus and Leonard I Wiebe

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.