In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine

Item Type:	Article
Title:	In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine
Creators Name:	Bijnsdorp, I.V. and Schwendener, R.A. and Schott, H. and Fichtner, I. and Smid, K. and Schott, S. and Laan, A.C. and Peters, G.J.
Abstract:	Multidrugs have the potential to bypass resistance. We investigated the in vitro activity and resistance circumvention of the multidrug cytarabine-L-fluorodeoxyuridine (AraC-L-5FdU), linked via a glycerophospholipid linkage. Cytotoxicity was determined using sensitive (A2780, FM3A/0) and resistant (AG6000, AraC resistant, deoxycytidine kinase deficient; FM3A/TK-, 5FdU resistant, thymidine kinase deficient) cell lines. Circumvention of nucleoside transporter and activating enzymes was determined using specific inhibitors, HPLC analysis and standard radioactivity assays. AraC-L-5FdU was active (IC50: 0.03 microM in both A2780 and FM3A/0), had some activity in AG6000 (IC50: 0.28 microM), but no activity in FM3A/TK(-) (IC50: 18.3 microM). AraC-nucleotides were not detected in AG6000. 5FdU-nucleotides were detected in all cell lines. AraC-L-5FdU did not inhibit TS in FM3A/TK(-) (5%). Since phosphatase/nucleotidase-inhibition reduced cytotoxicity 7-70-fold, cleavage seems to be outside the cell, presumably to nucleotides, and then to nucleosides. The multidrug was orally active in the HT-29 colon carcinoma xenografts which are resistant toward the single drugs.
Keywords:	Multidrugs, Cytarabine, Fluorodeoxyuridine, Resistance, Animals, Mice
Source:	Nucleosides Nucleotides & Nucleic Acids
ISSN:	1525-7770
Publisher:	Taylor & Francis
Volume:	26
Number:	10-12
Page Range:	1619-1624
Date:	5 December 2007
Official Publication:	https://doi.org/10.1080/15257770701548931
PubMed:	View item in PubMed

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