DEVELOPMENT OF VINCRISTINE RESISTANCE AND INCREASED SENSITIVITY TO CYCLOSPORINE-A AND VERAPAMIL IN THE HUMAN U-937 LYMPHOMA CELL-LINE WITHOUT OVEREXPRESSION OF THE 170-KDA P-GLYCOPROTEIN

A vincristine (Vcr)-resistant subline of the human histiocytic lymphoma cell line U-937 (U-937-vcr) has been established and characterized with respect to its phenotypic features, including growth rate, surface marker expression and ability to respond to differentiation-inducing agents. The sensitivity of U-937-vcr cells to the direct cytotoxicity of cyclosporin A (CsA) and verpamil (Ver), and the capacity of these drugs to modify Vcr resistance, were also examined. The U-937-vcr cells exhibited a more than 200-fold resistance to Vcr, and cross-resistance to vinorelbin and taxol. Also, there was a slight cross-resistance to colchicin, doxorubicin and VP16. However, the response of U-937-vcr to CsA or Ver alone was substantially altered, with a marked decrease in their respective IC(50)s. The U-937-vcr cells did not show increased levels of pgp 170. We conclude that the development of Vcr resistance was not associated with a change in the major phenotypic properties of the U-937 cell line, and that resistance modifier hypersensitivity was not associated with increase in pgp 170 expression. (C) 1994 Wiley-Liss, Inc.