DIRECT INTERACTION BETWEEN VERAPAMIL AND DOXORUBICIN CAUSES THE LACK OF REVERSAL EFFECT OF VERAPAMIL ON P-GLYCOPROTEIN MEDIATED RESISTANCE TO DOXORUBICIN IN-VITRO USING L1210 VCR CELLS/

Mouse leukemic cell subline L1210/VCR exerts expressive multidrug resi stance (MDR) that is mediated by P-glycoprotein. Cells originally adap ted to vincristine are also extremely resistant to doxorubicin. Resist ance to both vincristine and doxorubicin is connected with depression of drug uptake. While resistance of L1210 cells to vincristine could b e reversed by verapamil as chemosensitizer. resistance of cells to dox orubicin was insensitive to verapamil. Action of verapamil (well-known inhibitor of PGP activity) on multidrug resistance was often used as evidence that MDR is mediated by PGP. From this point it may be possib le that the resistance of L1210/VCR cells to vincristine is mediated b y PGP and the resistance to doxorubicin is mediated by other PGP-indep endent system. Another and more probable explanation of different effe ct of verapamil on resistance of L1210/VCR cells to vincristine and do xorubicin may be deduced from the following fact: Using UV spectroscop y we found that doxorubicin dissolved in water buffered medium interac ts effectively with verapamil. This interaction may be responsible for the decrease of concentration of both drugs in free effective form an d consequently for higher survival of cells. In contrast to doxorubici n vincristine does not give any interaction with verapamil that is mea surable by UV spectroscopy and resistance of L1210/VCR cells to vincri stine may be fully reversed by verapamil.