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Rose, Jayna M.; Peckham, Sara L.; Scism, Jamie L.; Audus, Kenneth L.

doi:10.1023/a:1022485026198

Cited by 25 publications

(3 citation statements)

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“…We have previously demonstrated that Pgp is expressed in primary cultures of BMECs . Other researchers have demonstrated that Taxol does not cross the endothelial lining of the in vivo BBB due to the presence of Pgp 12-14 localized on the blood-facing surface .…”

Section: Discussionmentioning

confidence: 95%

“…The culture medium was changed every other day after seeding until a confluent monolayer was formed as determined by light microscopy. Experiments were performed in phosphate-buffered saline supplemented with calcium and glucose (PBSA), pH 7.4, essentially as detailed earlier by Rose et al Briefly, the growth medium was first aspirated off and then the cells were rinsed three times with prewarmed (37 °C) PBSA. The monolayers were then either equilibrated in 1 mL of PBSA for 1 h at 37 °C for control experiments or equilibrated for 30 min in PBSA alone, followed by another 45 min preincubation with the a taxane.…”

Section: Methodsmentioning

confidence: 99%

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Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood−Brain Barrier in Vitro and in Situ

et al. 2005

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The purpose of this work was to introduce a chemical modification into the paclitaxel (Taxol) structure to reduce interactions with the product of the multidrug resistant type 1 (MDR1) gene, P-glycoprotein (Pgp), resulting in improved blood-brain barrier (BBB) permeability. Specifically, a taxane analogue, Tx-67, with a succinate group added at the C10 position of Taxol, was synthesized and identified as such a candidate. In comparison studies, Tx-67 had no apparent interactions with Pgp, as demonstrated by the lack of enhanced uptake of rhodamine 123 by brain microvessel endothelial cells (BMECs) in the presence of the agent. By contrast, Taxol exposure substantially enhanced rhodamine 123 uptake by BMECs through inhibition of Pgp. The transport across BMEC monolayers was polarized for both Tx-67 and Taxol with permeation in the apical to basolateral direction greater for Tx-67 and substantially reduced for Taxol relative to basolateral to apical permeation. Taxol and cyclosporin A treatments also did not enhance Tx-67 permeation across BMEC monolayers. In an in situ rat brain perfusion study, Tx-67 was demonstrated to permeate across the BBB at a greater rate than Taxol. These results demonstrate that the Taxol analogue Tx-67 had a reduced interaction with Pgp and, as a consequence, enhanced permeation across the blood-brain barrier in vitro and in situ.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood−Brain Barrier in Vitro and in Situ

et al. 2005

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“…20,21 This assay is a preliminary screen to evaluate a compound’s interaction with Pgp in bovine brain microvessel endothelial cells (BMECs). In this assay, rhodamine 123 is used as a surrogate Pgp substrate.…”

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confidence: 99%

Paclitaxel succinate analogs: Anionic and amide introduction as a strategy to impart blood–brain barrier permeability

Turunen

Oyetunji

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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A focused library of TX-67 (C10 hemi-succinate) analogs has been prepared, including C7 regioisomers, esters, amides, and one-carbon homologs. These were prepared to investigate whether the lack of TX-67 interaction with P-glycoprotein (Pgp) is due to the presence of the carboxylic acid moiety and whether this phenomenon was restricted to C10 analogs. Tubulin stabilization ability, cytotoxicity, and Pgp interactions were evaluated. All carboxylic acid analogs and several of the amides had no apparent interactions with Pgp at the concentrations used, whereas the ester variants displayed characteristics of Pgp substrates. Furthermore, it was demonstrated that hydrogen-bonding properties were significant with respect to Pgp interactions. Calculations of LogD and cross-sectional areas revealed that these analogues are predicted to partition into the membrane and can compete for Pgp binding sites. The anionic and amide introduction strategy may allow for delivery of paclitaxel into the CNS and may be a potential approach for the delivery of other, structurally complex and lipophilic non-CNS permeable drugs.Paclitaxel (Taxol, 1, Figure 1), a structurally complex natural product derived from the bark of the Pacific Yew, is one of the most studied and active anti-cancer agents known. 1-3 Although its clinical success is remarkable, the efficacy of the parent compound has limitations. 4,5One such shortcoming is paclitaxel's inability to cross the blood-brain barrier (BBB). 6,7 Accordingly, paclitaxel is not an effective treatment for primary or metastatic brain cancer despite its potent anti-proliferative activity. In addition to paclitaxel's well known anti-tumor properties, it has been shown to protect primary cortical neurons from beta amyloid (Aβ)-induced cell death as well as being non-toxic to primary cortical neurons. 8 Indeed, a paclitaxel derivative that could permeate the CNS is highly desirable from both the standpoint of chemotherapy as well as an investigational therapy for neurofibrillary pathology.Correspondence to: Gunda I. Georg. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A primary mechanism limiting the distribution of paclitaxel and other highly lipophilic substances into the brain is active efflux by the multidrug resistance gene product 1 (MDR1) P-glycoprotein (Pgp). 9-11 We have recently described a series of recognition elements required for Pgp interactions based upon the analysis of over one hundred known Pgp substrates. 12-14 This analysis revealed clusters of spatially distinct hydrogen bond acceptor units, which correlated, in their relativ...

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