Resistant Tumor Cells Modulation of Drug Sensitivity by Dipyridamole in Multidrug

The concept of overcoming multidrug 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 (I)I'M) to synergistically enhance drug sensitivity in drug-sensitive KB-3-1 cells and their drug-resistant variants, KB-GRC1 and KBV1 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 HYB241, directed at a V/, 180,000 form of the nuli-1 gene product, correlated with drug resistance for all three drugs (r > 0.92). DI'M and verapamil elevated the steady state content (('„,) of VBL, but there was no corre lation between elevation of C,, and the extent of synergy observed. I»I'M enhanced the cytotoxicity of VBL and COL in a synergistic manner in KB-GRC1 cells, and in KBV1 cells DPM interacted synergistically with VBL. VPL was synergistic with VBL only in KB-GRC1 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 rniJrl, synergy was observed, and it was greatest for the cytotoxic agent for which expression of nulrl produced the greatest foldresistance and enhancement of ( ,.,. However, neither the level of resist ance, the level of expression of nulrl, 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.