The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers

✍ Scribed by Jonathan K. Tunggal; Tricia Melo; James R. Ballinger; Ian F. Tannock

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: French
• Weight: 191 KB
• Volume: 86
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(20000401)86:1<101::aid-ijc16>3.0.co;2-i

✦ Synopsis

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.