Comparative cytotoxicities of a series of ellipticine and olivacine derivatives on multidrug resistant cells of human and murine origins.
The MDR P-glycoprotein has been described as a major factor of multidrug resistance. This transmembrane glycoprotein acts like an energy dependent efflux pump which possesses a broad specificity. It seems to be acting as a pump requiring drug fixation prior to extrusion. With the aim of investigating which parameters influence the recognition of drugs by the MDR system, we have determined the toxicities of different drugs on human and murine sensitive and resistant cell lines. For this purpose we have isolated and characterized a human adriamycin-resistant cell line, CEM/Adr, which presents an MDR phenotype. The tested drugs were ellipticine and olivacine derivatives which differ through discrete lateral chain substitutions. The influence of lateral chain lipophilicity and nitrogen quaternarization on drug recognition was studied. Small modifications in the chemical structure of the drugs have induced large changes in their toxicities and in the cross-resistance levels of the MDR cells to the tested compounds. The cross-resistances of the murine and human cells to the various compounds were strikingly different. The validity of murine screening models in the selection of anti-tumor drugs for human therapy must therefore be questioned.
Chevallier-Multon
M C
MC
Laboratoire de Pharmacologie Moléculaire, U.A. 147 CNRS, Villejuif, France.
Jacquemin-Sablon
A
A
Besselièvre
R
R
Husson
H P
HP
Le Pecq
J B
JB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004611:Ellipticines / Q000494:pharmacology*; D005784:Gene Amplification; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050356:Lipid Metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004611:Ellipticines; D008562:Membrane Glycoproteins; C011521:olivacine; D004317:Doxorubicin