Modulation of P-glycoprotein-mediated doxorubicin resistance in canine cell lines.
OBJECTIVE
To characterize the chemosensitivity of wild type and multidrug resistant canine cell lines and determine the relative potency of the P-glycoprotein (Pgp) modulators verapamil, tamoxifen and a cyclosporin-A analog (PSC833).


METHODS
The dose required to reduce cell proliferation to 50% of control (ED50) for doxorubicin (DOX) and cisplatin was determined for canine cell lines 4TG11-50c, OS2.4wt, OS2.4DX and the human cell line MCF7/DX. The effect of Pgp chemomodulators on cytotoxicity was quantified by determining the dose modifying factor [DMF = (ED50 of Dox alone)/(ED50 of Dox + Modulator)]. Relative potency of modulators was defined as DMFMOD1/DMFMOD2. Pgp function was assessed by DiOC2 dye retention and by accumulation of DOX after chemomodulator addition.


RESULTS
All cell lines were equally cisplatin sensitive but varied in doxorubicin resistance. PSC833 was 12X, 5X and 2X more potent than tamoxifen in 4TG11-50c, OS2.4WT and OS2.4DX, respectively. Dye retention was a better indicator of chemomodulator-enhanced cytotoxicity than was DOX accumulation.


CONCLUSIONS
Pgp inhibition is cell line, modulator and concentration dependent but the cytotoxic potency of a modulator may be predicted by the extent of dye retention in canine drug resistant cell lines.
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North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606, USA. rlp24@cornell.edu
Hughes
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Huyan
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Sagris
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Trogdon
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M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004396:Coloring Agents / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004396:Coloring Agents; D003524:Cyclosporins; D013629:Tamoxifen; D004317:Doxorubicin; D014700:Verapamil; D002945:Cisplatin; C070272:valspodar