Document Detail


AZT: a biochemical response modifier of methotrexate and 5-fluorouracil cytotoxicity in human ovarian and pancreatic carcinoma cells.
MedLine Citation:
PMID:  2025497     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In ovarian and pancreatic carcinoma cell lines, the activity of the salvage enzyme, thymidine kinase (EC 2.7.1.21), was 2- to 13-fold higher than that of the key enzyme of thymidylate de novo biosynthesis, thymidylate synthase (dTMP synthase, EC 2.1.1.45). AZT (3'-azido-3'-deoxythymidine, zidovudine) competitively inhibited thymidine kinase activity in extracts of human ovarian and pancreatic carcinoma cells, with Dixon plots yielding Ki = 1.1 microM in both cell lines. AZT (20 microM) yielded synergistic cytotoxicity with methotrexate (0.4 microM) in human pancreatic carcinoma cells in clonogenic assay and also with methotrexate (0.02 microM) in human ovarian carcinoma cells, as measured by cell counts. Thymidine (10 microM) and hypoxanthine (100 microM) reversed these inhibitions. AZT (20 or 40 microM) also provided synergistic cytotoxicity with 5-fluorouracil (0.5 and 1.0 microM) in human pancreatic carcinoma cells in clonogenic assay. These studies suggest a new role for AZT, which, as an inhibitor of thymidine salvage, should be useful as a biochemical response modifier to provide a synergistic clinical anticancer impact on de novo biosynthesis of thymidylates in conjunction with methotrexate or 5-fluorouracil.
Authors:
G Weber; M Nagai; N Prajda; H Nakamura; T Szekeres; E Olah
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer communications     Volume:  3     ISSN:  0955-3541     ISO Abbreviation:  Cancer Commun.     Publication Date:  1991 Apr 
Date Detail:
Created Date:  1991-06-07     Completed Date:  1991-06-07     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8916730     Medline TA:  Cancer Commun     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  127-32     Citation Subset:  IM; X    
Affiliation:
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding, Competitive
Cell Line
Dose-Response Relationship, Drug
Drug Synergism
Female
Fluorouracil / pharmacology*
Humans
Hypoxanthine
Hypoxanthines / pharmacology
Methotrexate / pharmacology*
Ovarian Neoplasms / drug therapy*
Pancreatic Neoplasms / drug therapy*
Rats
Thymidine / pharmacology
Thymidine Kinase / biosynthesis,  drug effects
Tumor Cells, Cultured
Zidovudine / pharmacology*
Grant Support
ID/Acronym/Agency:
CA-42510/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Hypoxanthines; 30516-87-1/Zidovudine; 50-89-5/Thymidine; 51-21-8/Fluorouracil; 59-05-2/Methotrexate; 68-94-0/Hypoxanthine; EC 2.7.1.21/Thymidine Kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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