Paclitaxel Disposition in Plasma and Central Nervous Systems of Humans and Rats With Brain Tumors

Glantz, Michael; Choy, Hak; Kearns, Cristin; Mills, P.; Wahlberg, Lars U.; Zuhowski, Eleanor G.; Calabresi, Paul; Egorin, Merrill J.

doi:10.1093/jnci/87.14.1077

Cited by 95 publications

(55 citation statements)

References 23 publications

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“…The fact that enhanced levels of free bax in LN-229 and T98G cells are associated with increased susceptibility to CD95 ligand is in perfect agreement with our previous observation that ectopic expression of bcl-2 in these cells attenuates the cytotoxic effects of agonistic CD95 antibodies (Weller et al, 1995b) and natural CD95 ligand (Roth et al, 1997). CD95 ligand-based proapoptotic immunotherapy of malignant glioma is a promising novel option for the management of malignant gliomas (Weller et al, 1994(Weller et al, , 1995a Immunochemotherapy of malignant glioma 411 taxol (Glantz et al, 1995b). For reasons outlined above, both CD95 ligand and taxol are likely to be maximally effective when administered using a locoregionary approach.…”

Section: Discussionsupporting

confidence: 84%

“…Based on promising studies on the effects of taxol on cultured glioma cells Silbergeld et al, 1995) and glioma xenografts (Riondel et al, 1992), several clinical studies of taxol for human malignant glioma patients have been conducted (Chamberlain and Kormanik, 1995;Glantz et al, 1995a; Prados et al, 1996). The disappointing results of these studies are probably partly due to the poor penetration of taxol into the brain at doses that are tolerated when given systemically (Glantz et al, 1995b). Although taxol may penetrate pathological vessel walls within tumour tissue much more efficiently than intact brain vessel walls (Heimans et al, 1994), it is clearly desirable to expose as many tumour cells to taxol as long as possibly achievable.…”

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confidence: 99%

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Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

Roth

Wagenknecht²,

Grimmel³

et al. 1998

Br J Cancer

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Summary The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

Roth

Wagenknecht²,

Grimmel³

et al. 1998

Br J Cancer

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“…In the current study, an increase in the levels of CD11b-IR microglia and GFAP-IR astrocytes was first observed at day six days post-infusion in the dorsal horn of the spinal cord of paclitaxel-treated rats. Paclitaxel has a limited ability to cross the blood brain barrier in that the plasma/cerebrospinal fluid ratio of paclitaxel is greater than 500:1 (Glantz et al, 1995). Therefore, the present data suggest that this glial activation occurs as a result of degeneration of central terminals of injured primary afferent fibers (Kapadia & LaMotte, 1987;Aldskogius et al, 1999) or possibly due to the spinal release of factors from injured sensory neurons (Tsuda et al, 2005) rather than due to a direct effect of paclitaxel on spinal cord neurons.…”

Section: Markers Indicative Of Microglia and Astrocyte Activation Arementioning

confidence: 66%

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

et al. 2007

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Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglion (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68+ macrophages in the DRG and sciatic nerve, ATF3 expression in S100β+ Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein in the spinal cord were not observed until day 6 post infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.

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“…infusion, the cerebrospinal fluid levels reach only 0.12-8.3% of those present in concomitant plasma samples. 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).…”

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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Paclitaxel Disposition in Plasma and Central Nervous Systems of Humans and Rats With Brain Tumors

Abstract: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

Cited by 95 publications

References 23 publications

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

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

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