title: The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers.
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.
authors.affiliation: Department of Medicine and Medical Biophysics, Ontario Cancer Institute, University of Toronto, Canada.
authors.forename: J K
authors.initials: JK
authors.lastname: Tunggal
authors.forename: T
authors.initials: T
authors.lastname: Melo
authors.forename: J R
authors.initials: JR
authors.lastname: Ballinger
authors.forename: I F
authors.initials: IF
authors.lastname: Tannock
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D013395:Sucrose / Q000493:pharmacokinetics; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D013395:Sucrose; D004317:Doxorubicin; D017256:Technetium Tc 99m Sestamibi; D014700:Verapamil; D005472:Fluorouracil