Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition

Zhou, Shu Feng

doi:10.1080/00498250701867889

Cited by 522 publications

(323 citation statements)

References 177 publications

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“…One strategy is combination chemotherapy with agents that have different mechanisms of action and are structurally distinct; however, tumor cells respond to this approach by becoming multidrug resistant (3). Because P-gp, the product of mdr1, has been implicated in multidrug resistance of various cancers (21), another possible approach to overcome resistance is to use P-pg inhibitors to increase intracellular accumulation of chemotherapeutics that are substrates to this transporter (36). Although these agents have shown much promise in vitro, nonspecific toxicities due to interference with clearance or metabolism of chemotherapeutics in healthy tissues have thus far limited their clinical utility (36).…”

Section: Discussionmentioning

confidence: 99%

“…Intermittent 1Â/wk docetaxel administration led to an upregulation of various genes implicated in docetaxel resistance. Particularly high upregulation was observed for mdr1 (P-gp), which leads to multidrug resistance and, ultimately, treatment failure (21). This effect was more pronounced in HeyA8-MDR xenografts, which reflect recurrent, refractory disease.…”

Section: Discussionmentioning

confidence: 99%

“…Members of the adenosine triphosphate-binding cassette (ABC) transporter superfamily have been associated with drug resistance by decreasing the intracellular accumulation of hydrophobic chemotherapeutics (20). Of these, the product of the multidrug resistance 1 (mdr1) gene, P-glycoprotein (P-gp), is one of the key molecules leading to cancer multidrug resistance (21). Overexpression of mdr1 has been shown in refractory ovarian cancer tumor cells (22).…”

Section: Introductionmentioning

confidence: 99%

“…P-gp is capable of transporting a variety of substrates ranging in size from 300 to 2,000 Da (20). Cancer cells exhibiting upregulation of P-gp become resistant to multiple structurally and mechanistically unrelated chemotherapeutic agents and are classified as multidrug resistant (21). Because intracellular drug accumulation is the basic requirement for chemotherapeutics to exert their effects, the upregulation of drug efflux transporters that hinder the acquisition of proper intracellular drug levels is of key importance in the development of drug resistance (1,3).…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Souza

Zahedi

Badame

et al. 2011

Molecular Cancer Therapeutics

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Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1Â/wk or 3Â/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including b-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1Â/wk or 3Â/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3Â/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Souza

Zahedi

Badame

et al. 2011

Molecular Cancer Therapeutics

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“…Unfortunately, high resolution structural information of mammalian ABC-transporters including BSEP remains elusive (82).…”

Section: Discussionmentioning

confidence: 99%

Recent insights into the function and regulation of the bile salt export pump (ABCB11)

Stieger

2009

Current Opinion in Lipidology

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Overview of Experimental Models of the Blood‐Brain Barrier in CNS Drug Discovery

Palmer¹,

Alavijeh

2013

CP Pharmacology

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The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF). In this overview, we review techniques to measure BBB permeation, which is evidenced by the free concentration of compound in brain ISF over time. We consider a number of measurement techniques, including in vivo microdialysis and brain receptor occupancy following perfusion. Consideration is also given to the endothelial and nonendothelial cell systems used to assess both the BBB permeation of a test compound and its interactions with egress transporters, and computer models employed for predicting passive permeation and the probability of interactions with BBB transporters.

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Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition

Cited by 522 publications

References 177 publications

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Recent insights into the function and regulation of the bile salt export pump (ABCB11)

Overview of Experimental Models of the Blood‐Brain Barrier in CNS Drug Discovery

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