Modulation of drug sensitivity by dipyridamole in multidrug resistant tumor cells in vitro Journal Article


Authors: Shalinsky, D. R.; Andreeff, M.; Howell, S. B.
Article Title: Modulation of drug sensitivity by dipyridamole in multidrug resistant tumor cells in vitro
Abstract: The concept of overcoming multidnig resistance using modulators is based on the hypothesis that there will be a synergistic interaction between the modulator and the cytotoxic agent. We examined the ability of dipyridamole (DPM) to synergistically enhance drug sensitivity in drug-sensitive KB-3-1 cells and their drug-resistant variants, KB-GRCl and KBVI cells, using median effect analysis to produce a quantitative measure of the extent of synergy. The drug-resistant variants were resistant to vinblastine (VBL), colchicine (COL), and etoposide (VP-16) in the order VBL >COL >VP-16 on the basis of 50% inhibitory concentration values obtained by clonogenic assay with continuous drug exposure. The extent of staining with the monoclonal antibody HYB-241, directed at a M., 180,000 form of the mdrl gene product, correlated with drug resistance for all three drugs (r >0.92). DPM and verapamil elevated the steady state content (C�) of VBL, but there was no correlation between elevation of C� and the extent of synergy observed. DPM enhanced the cytotoxicity of VBL and COL in a synergistic manner in KB-GRCl cells, and in KBVI cells DPM interacted synergistically with VBL. VPL was synergistic with VBL only in KB-GRCl cells. No synergy was observed in the parental KB-3-1 line. These data indicate that, although both DPM and verapamil can increase C� in cells not expressing P-glycoprotein, such an increase was not associated with synergy. In cells expressing mi/r/, synergy was observed, and it was greatest for the cytotoxic agent for which expression of mdrl produced the greatest fold-resistance and enhancement of C�. However, neither the level of resistance, the level of expression of mdrl nor the ability of the modulator to alter C� accurately predicted whether the interaction would be truly synergistic. We conclude that additional factors determine the nature of the drug interaction. © 1990, American Association for Cancer Research. All rights reserved.
Keywords: human cell; carcinoma, squamous cell; drug potentiation; gene; cell survival; etoposide; neoplasm proteins; drug resistance; vinblastine; drug synergism; membrane glycoproteins; tumor cell line; clonogenic assay; drug sensitivity; verapamil; p-glycoprotein; in vitro; colchicine; drug interaction; dipyridamole; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
Journal Title: Cancer Research
Volume: 50
Issue: 23
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 1990-12-01
Start Page: 7537
End Page: 7543
Language: English
PUBMED: 1979245
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 27 January 2020 -- Source: Scopus
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