Cytotoxic activity of several unrelated drugs on L1210 mouse leukemic cellsublines with P-glycoprotein (PGP) mediated multidrug resistance (MDR) phenotype. A QSAR study

L1210/VCR-1 and L1210/VCR-2 cell lines are multidrug resistant (MDR) sublin es obtained by adaptation of mouse leukemic cell line L1210 to vincristine and, the development of MDR in these cell lines has been found to be associ ated with an overexpression of P-glycoprotein (PGP). In the present work we studied the relationship between the structure of 15 cytotoxic active subs tances (drugs) and their cytotoxicities on L1210/VCR-1 and L1210/VCR-2 resi stant cell lines. The resistance of these MDR cells to the respective drugs was expressed as the ratio of IC50 Values obtained for resistant and sensi tive cells. These values of resistance were correlated with the following p hysico-chemical constants of the test substances. binding energy, E-bind; t otal energy of the molecule, E-sum; aromaticity, K-pi; molecular weight, M- w; acidobasic constant, pK(a); partition coefficient in water/octanol two p hase system, log(p). It has been found that according to the cytotoxic effe cts the tested drugs may be divided into three groups: (i) drugs with highe r cytotoxicity to the resistant cell lines as to sensitive cells (collatera l hypersensitivity); (ii) drugs exhibiting approximately similar effects on sensitive and resistant cell lines; (iii) drugs with weaker cytotoxicity t o resistant cells than to sensitive cells. No direct correlations with any physico-chemical constant described above could be established for cell res istance to the drug studied. However, resistance: values could be fitted by multiple exponential regression with all described physico-chemical consta nts implied as six independent variables. The fatter procedure made us to c onclude that the ability of a drug to be a substrate for PGP is connected w ith its fulfilling the following criteria. (i) flexible structure of its mo lecule; (ii) molecular weight lower than similar to 1300 g/mol; (iii) nonpr otonized character at pH 7.0.