ISSN:
0730-2312
Keywords:
10-EDAM
;
dipyridamole
;
methotrexate
;
lung cancer
;
Life Sciences
;
Molecular Cell Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
10-ethyl-10-deazaaminopterin (10-EDAM) is a rationally designed derivative of the antifolate, methotrexate (MTX). In a number of tumor models these design features have resulted in an improved spectrum of antiproliferative activity as compared with the parent compound. Using an MTT growth assay, we compared in vitro antiproliferative activity of 10-EDAM with MTX in eight lung cancer cell lines. Growth was inhibited in all lines tested by clinically achievable concentrations of 10-EDAM (0.1-1,000 nM). 10-EDAM was more cytotoxic than MTX at the same concentrations in all eight lung cancer cell lines. In an effort to enhance the antiproliferative effect, we evaluated the addition of dipyridamole (DPM), an inhibitor of nucleoside transport, to 10-EDAM (0.1-10 μm). DPM decreased the concentration of 10-EDAM required to cause 50% growth inhibition (IC50) in all eight cell lines tested. This supperssion was statistically significant by 2-sided sign test (P = .0078). By contrast, the IC50 of MTX was decreased in only two of the eight cell lines when DPM was added (0.1-10 μM). In defined thymidine depleted media, cell kill by the combination of 10-EDAM and DPM was no greater than 10-EDAM alone, consistent with the possibility that DPM exerts some of its effect by inhibition of extrinsic nucleoside salvage. In consideration of the published activity of 10-EDAM in lung cancer and the modest clinical toxicity of DPM based biochemical modulation, we conclude the current in vitro data provide justification for clinical evaluation of this combination in patients with lung cancer. © 1996 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcb.240630512
