Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl- 10-deazaaminopterin (10-EDAM) against human lung cancer cell lines

Mary Pat Dearing, Mae Jean Englee-Miller, Robert A. Kratzke, Barnett S. Kramer, Edward Chu, John Weinstein, Michael Anderson, David Venzon, James L. Mulshine, Adi F. Gazdar

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 suppression 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.

Original languageEnglish (US)
Pages (from-to)165-172
Number of pages8
JournalJournal of Cellular Biochemistry
Volume62
Issue numberSUPPL. 24
DOIs
StatePublished - 1996

Fingerprint

Dipyridamole
Lung Neoplasms
Cells
Cell Line
Methotrexate
Nucleosides
Inhibitory Concentration 50
Growth
Folic Acid Antagonists
edatrexate
Salvaging
Thymidine
Toxicity
Tumors
Assays
Modulation
Derivatives

Keywords

  • 10-EDAM
  • dipyridamole
  • lung cancer
  • methotrexate

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl- 10-deazaaminopterin (10-EDAM) against human lung cancer cell lines. / Dearing, Mary Pat; Englee-Miller, Mae Jean; Kratzke, Robert A.; Kramer, Barnett S.; Chu, Edward; Weinstein, John; Anderson, Michael; Venzon, David; Mulshine, James L.; Gazdar, Adi F.

In: Journal of Cellular Biochemistry, Vol. 62, No. SUPPL. 24, 1996, p. 165-172.

Research output: Contribution to journalArticle

Dearing, Mary Pat ; Englee-Miller, Mae Jean ; Kratzke, Robert A. ; Kramer, Barnett S. ; Chu, Edward ; Weinstein, John ; Anderson, Michael ; Venzon, David ; Mulshine, James L. ; Gazdar, Adi F. / Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl- 10-deazaaminopterin (10-EDAM) against human lung cancer cell lines. In: Journal of Cellular Biochemistry. 1996 ; Vol. 62, No. SUPPL. 24. pp. 165-172.
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abstract = "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 suppression 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.",
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AU - Englee-Miller, Mae Jean

AU - Kratzke, Robert A.

AU - Kramer, Barnett S.

AU - Chu, Edward

AU - Weinstein, John

AU - Anderson, Michael

AU - Venzon, David

AU - Mulshine, James L.

AU - Gazdar, Adi F.

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