title: A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier.
abstract: Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.
authors.affiliation: Positron Emission Tomography Center, Department of Medical Oncology, Groningen University Hospital, The Netherlands.
authors.forename: N H
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: L
authors.initials: L
authors.lastname: Eriks-Fluks
authors.forename: W T
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: G A
authors.initials: GA
authors.lastname: Hospers
authors.forename: A T
authors.initials: AT
authors.lastname: Willemsen
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
authors.forename: E J
authors.initials: EJ
authors.lastname: Franssen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001923:Brain Chemistry; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D051381:Rats; D011923:Rats, Nude; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016572:Cyclosporine; D014700:Verapamil; D003630:Daunorubicin