In Vivo and in Vitro Activity And Mechanism Of Action of the Multidrug Cytarabine-L-Glycerylyl-Fluorodeoxyuridine |
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| Authors: | Irene V. Bijnsdorp Reto A. Schwendener Herbert Schott Iduna Fichtner Kees Smid Sarah Schott |
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| Affiliation: | 1. Molecular Cell Biology, Institute of Molecular Cancer Research, University of Zürich , Zürich, Switzerland;2. Institut für Organische Chemie I , Tübingen, Germany;3. Max Delbrück Center for Molecular Medicine , Berlin, Germany;4. Department of Medical Oncology. VU University Medical Center , Amsterdam, the Netherlands |
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| 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 μM in both A2780 and FM3A/0), had some activity in AG6000 (IC50: 0.28 μ M), but no activity in FM3A/TK? (IC50: 18.3 μM). 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. |
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| Keywords: | Multidrugs cytarabine fluorodeoxyuridine resistance |
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