Influence of cell concentration in limiting the therapeutic benefit of P-glycoprotein reversal agents.
Pharmacological reversal of multidrug resistance (MDR) has been demonstrated frequently in tissue culture, but there has been minimal evidence of therapeutic effectiveness for solid tumours of animals, or in clinical trials. The concentration of cells in solid tumours is approx. 10(9) cells/ml but typically 10(5)-10(6) cells/ml in tissue culture. We investigated, therefore, the influence of cell concentration in culture on the ability of verapamil and cyclosporin A to increase the sensitivity of MDR-expressing cells to doxorubicin. Our data indicate that: 1. the uptake of the MDR substrates, doxorubicin and 99mTc-SestaMIBI, and the toxicity of doxorubicin decrease at higher cell concentration; 2. the effect of reversal agents on uptake and cytotoxicity of MDR substrates decreases markedly at higher cell concentration; 3. cell concentration effects are not overcome by continuous replenishment of drug to maintain a stable extracellular concentration. Our results suggest one mechanism which may contribute to the failure to observe reversal of MDR in animals, or in patients bearing established solid tumours.
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*