title: In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine.
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.
authors: Molecular Cell Biology, Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors: Irene V
authors: IV
authors: Bijnsdorp
authors: Reto A
authors: RA
authors: Schwendener
authors: Herbert
authors: H
authors: Schott
authors: Iduna
authors: I
authors: Fichtner
authors: Kees
authors: K
authors: Smid
authors: Sarah
authors: S
authors: Schott
authors: Adrie C
authors: AC
authors: Laan
authors: Godefridus J
authors: GJ
authors: Peters
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020128:Inhibitory Concentration 50; D051379:Mice; D008815:Mice, Inbred Strains; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C527204:AraC-L-5FdU; D003857:Deoxyuridine