Dynamics of multidrug resistance: P-glycoprotein analyses with positron emission tomography

Multidrug resistance (MDR) is characterized by the occurrence of cross-resistance to a broad range of structurally and functionally unrelated drugs. Several mechanisms are involved in MDR. One of the most well-known mechanisms is the overexpression of P-glycoprotein (P-gp), encoded by the MDR1 gene...

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Bibliographic Details
Published in:Methods (San Diego, Calif.) Calif.), 2002-07, Vol.27 (3), p.228-233
Main Authors: Hendrikse, N.H, Vaalburg, Willem
Format: Article
Language:English
Subjects:
Adult
Animals
ATP-Binding Cassette, Sub-Family B, Member 1 - analysis
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Carcinoma, Small Cell - metabolism
Carcinoma, Small Cell - pathology
Drug Resistance, Multiple - physiology
Female
Humans
In vivo
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
Middle Aged
Multidrug resistance
P-glycoprotein
Pharmacokinetics
Positron emission tomography
Rats
Rats, Nude
Tissue Distribution
Tomography, Emission-Computed - methods
Tumor Cells, Cultured
Verapamil - pharmacokinetics
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Summary:Multidrug resistance (MDR) is characterized by the occurrence of cross-resistance to a broad range of structurally and functionally unrelated drugs. Several mechanisms are involved in MDR. One of the most well-known mechanisms is the overexpression of P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the mdr1a and mdr1b genes in rodents. P-gp is extensively expressed in the human body, e.g., in the blood–brain barrier and also in solid tumor tissue. Overexpression of P-gp on tumor membranes might result in MDR of human tumors. To circumvent this resistant phenotype, several P-gp modulators such as cyclosporin A (CsA) are available. Competition between P-gp drugs and modulators results in decreased transport of the drug out of tumor tissue and an increased cellular level of these drugs. For effective clinical treatment it is important to have knowledge about P-gp functionality in tumors. Therefore, we have developed a method to measure the P-gp functionality in vivo with PET and [ 11 C] verapamil as a positron-emitting P-gp substrate. The results obtained in rodents and in cancer patients are described in this article.
ISSN:1046-2023
1095-9130
DOI:10.1016/S1046-2023(02)00079-8