| In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine. | |
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MedLine Citation:
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PMID: 18066839 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Irene V Bijnsdorp; Reto A Schwendener; Herbert Schott; Iduna Fichtner; Kees Smid; Sarah Schott; Adrie C Laan; Godefridus J Peters |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nucleosides, nucleotides & nucleic acids Volume: 26 ISSN: 1525-7770 ISO Abbreviation: Nucleosides Nucleotides Nucleic Acids Publication Date: 2007 |
Date Detail:
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Created Date: 2007-12-10 Completed Date: 2008-03-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100892832 Medline TA: Nucleosides Nucleotides Nucleic Acids Country: United States |
Other Details:
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Languages: eng Pagination: 1619-24 Citation Subset: IM |
Affiliation:
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Molecular Cell Biology, Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Antineoplastic Agents / chemistry, metabolism, pharmacology* Cell Line, Tumor Deoxyuridine / analogs & derivatives*, chemistry, metabolism, pharmacology Female Inhibitory Concentration 50 Mice Mice, Inbred Strains Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/AraC-L-5FdU; 951-78-0/Deoxyuridine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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