Linked Life Data

10344751

Source:http://linkedlifedata.com/resource/pubmed/id/10344751

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
1999-6-17
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
59
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2411-6
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10344751-Animals, pubmed-meshheading:10344751-Antibiotics, Antineoplastic, pubmed-meshheading:10344751-Blood-Brain Barrier, pubmed-meshheading:10344751-Brain Chemistry, pubmed-meshheading:10344751-Calcium Channel Blockers, pubmed-meshheading:10344751-Carcinoma, Small Cell, pubmed-meshheading:10344751-Cyclosporine, pubmed-meshheading:10344751-Daunorubicin, pubmed-meshheading:10344751-Drug Resistance, Multiple, pubmed-meshheading:10344751-Drug Resistance, Neoplasm, pubmed-meshheading:10344751-Humans, pubmed-meshheading:10344751-Lung Neoplasms, pubmed-meshheading:10344751-Male, pubmed-meshheading:10344751-Metabolic Clearance Rate, pubmed-meshheading:10344751-Neoplasm Proteins, pubmed-meshheading:10344751-Neoplasm Transplantation, pubmed-meshheading:10344751-Neoplasms, pubmed-meshheading:10344751-P-Glycoprotein, pubmed-meshheading:10344751-Rats, pubmed-meshheading:10344751-Rats, Nude, pubmed-meshheading:10344751-Recombinant Fusion Proteins, pubmed-meshheading:10344751-Tissue Distribution, pubmed-meshheading:10344751-Tumor Cells, Cultured, pubmed-meshheading:10344751-Verapamil
pubmed:year
1999
pubmed:articleTitle
A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier.
pubmed:affiliation
Positron Emission Tomography Center, Department of Medical Oncology, Groningen University Hospital, The Netherlands.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't