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Influence of cell concentration in limiting the therapeutic benefit of P‐glycoprotein reversal agents
Author(s) -
Tunggal Jonathan K.,
Ballinger James R.,
Tannock Ian F.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990531)81:5<741::aid-ijc13>3.0.co;2-g
Subject(s) - verapamil , doxorubicin , p glycoprotein , cell culture , pharmacology , extracellular , multiple drug resistance , toxicity , cytotoxicity , chemotherapy , efflux , cell , in vitro , cancer research , chemistry , medicine , biology , drug resistance , biochemistry , microbiology and biotechnology , calcium , genetics
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 99m Tc‐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. Int. J. Cancer 81:741–747, 1999. © 1999 Wiley‐Liss, Inc.