Cytotoxic activity of several unrelated drugs on L1210 mouse leukemic cell sublines 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) sublines 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 associated with an overexpression of P-glycoprotein (PGP). In the present work we studied the relationship between the structure of 15 cytotoxic active substances (drugs) and their cytotoxicities on L1210/VCR-1 and L1210/VCR-2 resistant cell lines. The resistance of these MDR cells to the respective drugs was expressed as the ratio of IC50 values obtained for resistant and sensitive cells. These values of resistance were correlated with the following physico-chemical constants of the test substances: binding energy, Ebind; total energy of the molecule, Esum; aromaticity, Kpi; molecular weight, Mw; acidobasic constant, pKa; partition coefficient in water/octanol two phase system, log(p). It has been found that according to the cytotoxic effects the tested drugs may be divided into three groups: (i) drugs with higher cytotoxicity to the resistant cell lines as to sensitive cells (collateral hypersensitivity); (ii) drugs exhibiting approximately similar effects on sensitive and resistant cell lines; (iii) drugs with weaker cytotoxicity to resistant cells than to sensitive cells. No direct correlations with any physico-chemical constant described above could be established for cell resistance to the drug studied. However, resistance values could be fitted by multiple exponential regression with all described physico-chemical constants implied as six independent variables. The latter procedure made us to conclude that the ability of a drug to be a substrate for PGP is connected with its fulfilling the following criteria: (i) flexible structure of its molecule; (ii) molecular weight lower than approximately 1,300 g/mol; (iii) nonprotonized character at pH 7.0.
Breier
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Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic. usrdtylo@savba.sk
Drobná
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Docolomansky
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Barancik
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014750:Vincristine