Paclitaxel (TAXOL®) concentrations in brain tumor tissue

Heimans, Jan J.; Vermorken, J. B.; Wolbers, J.G.; Eeltink, Corien; Meijer, Otto W.M.; Taphoorn, Martin J.B.; Beijnen, J. H.

doi:10.1093/oxfordjournals.annonc.a058736

Cited by 116 publications

(61 citation statements)

References 3 publications

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“…8 Our results suggest that repeated administration of oxycodone not only causes upregulation of P-gp, but also significantly affects the transport of paclitaxel across the BBB, liver, and kidney. These findings have potentially important implications on the therapeutic activity of paclitaxel especially in the treatment of brain, hepatic and renal tumors [19][20][21]39,40 when coadministered with oxycodone. It should be noted that oxycodone levels would have been quantified in the oxycodone tolerant animals if radiolabelled oxycodone was available.…”

Section: Discussionmentioning

confidence: 98%

“…For the management of cancer, oxycodone is usually coadministered with many chemotherapeutic agents, the majority of these agents are P-gp substrates. [19][20][21][22] Changes in P-gp expression upon repeated administration of oxycodone may affect the uptake, the distribution, and the potency of these chemotherapeutic agents which in turn may lead to ineffective cancer therapy. The goal of this study was to investigate the influence of multiple administration of oxycodone on the level of expression of P-gp in different tissues in Sprague Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

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Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Hassan

Myers

Lee

et al. 2007

Journal of Pharmaceutical Sciences

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Previous studies suggest that P-glycoprotein (P-gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P-gp affinity status of oxycodone, the P-gp expression, and the paclitaxel's tissue distribution in oxycodone-treated rats. P-gp ATPase assay, Caco-2 transepithelial permeability studies, and mdr1a/b (−/−) mice were used to assess the P-gp affinity status of oxycodone. P-gp expression was determined by Western blot analysis while [ 14 C] paclitaxel's distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P-gp ATPase activity in a concentration-dependant manner. The Caco-2 secretory transport of oxycodone was reduced from 3.64 ×10 −5 to 1.96 × 10 −5 cm/s (p <0.05) upon preincubation with the P-gp inhibitor, verapamil. The brain levels of oxycodone in mdr1a/b (+/+) were not detectable (<15 ng/mL) while in mdr1a/b (−/−) the average levels were 115 ± 39 ng/mL. The P-gp protein levels were increased by 1.3-4.0 folds while paclitaxel's tissue distributions were decreased by 38-90% (p <0.05) in oxycodone-treated rats. These findings display that oxycodone is a P-gp substrate, induces overexpression of P-gp, and affects paclitaxel's tissue distribution in a manner that may influence its chemotherapeutic activity.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Hassan

Myers

Lee

et al. 2007

Journal of Pharmaceutical Sciences

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“…Thus, the drug penetrates the blood-brain barrier poorly (Glantz et al, 1995). Despite this, there is at present some evidence that paclitaxel (Heimans et al, 1994). In line with this, several reports have indicated that the drug can be effective against experimental brain tumours, when it is delivered either from biodegradable polymer implants (Walter et al, 1996) or from liposome-encapsulated vehicles (Riondel et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Terzis

Thorsen²,

Heese³

et al. 1997

Br J Cancer

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Summary Paclitaxel (Taxol), an anti-cancer drug derived from Taxus species, was tested for its anti-migrational, anti-invasive and antiproliferative effect on two human glioma cell lines (GaMg and D-54Mg) grown as multicellular tumour spheroids. In addition, the direct effect of paclitaxel on glioma cells was studied using flow cytometry and scanning confocal microscopy. Both cell lines showed a dose-dependent growth and migratory response to paclitaxel. The GaMg cells were found to be 5-10 times more sensitive to paclitaxel than D-54Mg cells. Paclitaxel also proved to be remarkably effective in preventing invasion in a co-culture system in which tumour spheroids were confronted with fetal rat brain cell aggregates. Control experiments with Cremophor EL (the solvent of paclitaxel for clinical use) in this study showed no effect on tumour cell migration, cell proliferation or cell invasion. Scanning confocal microscopy of both cell lines showed an extensive random organization of the microtubules in the cytoplasm. After paclitaxel exposure, the GaMg and the D-54Mg cells exhibited a fragmentation of the nuclear material, indicating a possible induction of apoptosis. In line with this, flow cytometric DNA histograms showed an accumulation of cells in the G/M phase of the cell cycle after 24 h of paclitaxel exposure. After 48 h, a deterioration of the DNA histograms was observed indicating nuclear fragmentation.

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“…Although paclitaxel has shown potent in vitro activity in human glioma lines (12 -14), low concentrations of paclitaxel in human PBT samples and undetectable levels in normal brain tissue have been shown (15). Thus, the failure to achieve adequate paclitaxel deposition in a glioma with a partially intact BBB may account in part for paclitaxel's poor efficacy for PBT (16,17).…”

mentioning

confidence: 99%

Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

Fine

Chen

Balmaceda

et al. 2006

Clinical Cancer Research

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Purpose: Drug resistanceinbrain tumors is partially mediated by the blood-brainbarrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m 2 /i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

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Paclitaxel (TAXOL®) concentrations in brain tumor tissue

Abstract: These findings suggest that paclitaxel may have a place in brain tumor therapy. The low concentration in normal brain tissue, as observed in one patient, may suggest, however, that the drug does not cross the intact bloodbrain barrier.

Cited by 116 publications

References 3 publications

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

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