The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers |
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Authors: | Tunggal J K Melo T Ballinger J R Tannock I F |
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Affiliation: | Department of Medicine and Medical Biophysics, Ontario Cancer Institute, University of Toronto, Canada. |
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Abstract: | 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, 99mTc-sestaMIBI and 14C-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 14C-sucrose or of 3H-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. |
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