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The influence of expression of P‐glycoprotein on the penetration of anticancer drugs through multicellular layers
Author(s) -
Tunggal Jonathan K.,
Melo Tricia,
Ballinger James R.,
Tannock Ian F.
Publication year - 2000
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(20000401)86:1<101::aid-ijc16>3.0.co;2-i
Subject(s) - penetration (warfare) , p glycoprotein , cell culture , in vitro , cell , doxorubicin , chemistry , pharmacology , cancer research , biology , multiple drug resistance , microbiology and biotechnology , chemotherapy , drug resistance , medicine , biochemistry , genetics , operations research , engineering
The success of chemotherapy in the treatment of solid tumours may be limited by cellular mechanisms leading to drug resistance and/or by the slow penetration of drugs through tissue, resulting in a steep concentration gradient from tumour blood vessels. One mechanism leading to the development of multidrug resistance is overexpression of the membrane‐based export pump P‐glycoprotein (P‐gp). The relationship between expression of P‐gp by constituent cells and the penetration of P‐gp substrates through tissue was studied by comparing the penetration of P‐gp substrates through multicellular layers derived from either wild‐type or P‐gp overexpressing cell lines. P‐gp reversal agents were added to confirm the contribution of P‐gp in influencing the penetration of its substrates. Our data indicate: 1. penetration of the P‐gp substrates, 99m Tc‐sestaMIBI and 14 C‐doxorubicin, is greater through multicellular layers formed from P‐gp overexpressing cell lines as compared with wild‐type cells; 2. the addition of agents that inhibit the function of P‐gp results in decreased penetration of these substrates through multicellular layers with P‐gp expression. There was no effect of P‐gp reversal agents on penetration of 14 C‐sucrose or of 3 H‐5‐fluorouracil (non‐substrate controls). Our data suggest that the administration of agents that inhibit the function of P‐gp might have opposing effects on therapeutic index in solid tumours: increased sensitivity of perivascular tumour cells but decreased penetration of P‐gp substrates to more distal cells. These effects may explain, in part, the limited therapeutic benefit for solid tumours that has accrued from use of agents that reverse the effects of P‐gp. Int. J. Cancer 86:101–107, 2000. © 2000 Wiley‐Liss, Inc.