Structure-activity studies of amsacrine analogs in drug resistant human leukemia cell lines expressing either altered DNA topoisomerase II or P-glycoprotein.
In an attempt to characterize and overcome tumor cell resistance to amsacrine (m-AMSA), we studied the structure-activity relationships for amsacrine and seven of its analogs. Using the human leukemic cell line, CCRF-CEM, and its derivatives that express either P-glycoprotein (Pgp)-associated multidrug resistance (MDR) (CEM/VLB100) or altered topoisomerase II-associated MDR (at-MDR) (CEM/VM-1), we assessed antitumor effects of these drugs in a 48-hr growth inhibition assay. We also measured drug-topoisomerase II interactions in an intact cell assay that permits quantitation of drug-stabilized DNA-topoisomerase II complexes. We found that among the tested compounds, amsacrine has an intermediate effect on cell growth in all three cell lines. The CEM/VM-1 cells were 8.6-fold cross-resistant to m-AMSA, and the cross-resistance to the analogs was from 3.0- to 10.5-fold. In the CEM/VLB100 cells, the resistance pattern was different: several analogs, including amsacrine, showed little or no cross-resistance (0.5- to 2.8-fold), whereas for those compounds with substituents at position 3 on the acridine ring, resistance was relatively higher (9.9- or 16.2-fold). Substituents at this position substantially decrease the lipophilicity of the two compounds examined, probably because they both contain amino groups that would be charged at physiologic pH. Compound 12489, having a 1'-NHSO2C6H4NH2 substituent, was very potent in the three cell lines, showing only a slightly higher IC50 value in the CEM/VM-1 line and a lower IC50 value in the CEM/VLB100 and in the CEM cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
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Granzen
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Graves
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Baguley
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Danks
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Beck
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000677:Amsacrine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015195:Drug Design; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D000677:Amsacrine; D004247:DNA; D004250:DNA Topoisomerases, Type II