The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel

Mm, Malingré; Beijnen, J. H.; Rosing, Hilde; Fj, Koopman; O, van Tellingen; Duchin, Kenneth L.; Ww, ten Bokkel Huinink; Swart, M; Lieverst, Jan A.; Jh, Schellens

doi:10.1097/00001813-200104000-00008

Cited by 26 publications

(14 citation statements)

References 25 publications

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“…The minimally effective plasma paclitaxel concentration in patients is reported to be 100 nM (Sekine et al, 1996;Malingre et al, 2001;Mross et al, 2006;Kobayashi et al, 2006). Both 100 and 7 nM paclitaxel concentrations were analyzed but only immunofluorescence data from cells treated with 100 nM paclitaxel were shown.…”

Section: Discussionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of α-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of α-tubulin in mitotic cells showed spindle formation in arsenite-and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. γ-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

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Section: Discussionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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“…It is clinically applied for the treatment of ovarian, breast, stomach and non-small cell lung cancer (2,3). When used clinically, it causes severe side-effects such as leucopenia.…”

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confidence: 99%

Partial Protection of Paclitaxel-induced Neurotoxicity by Antioxidants

Hara

Sakagami

Shi

et al. 2018

In Vivo

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Abstract. Background Paclitaxel is an anticancer drug that inhibits calcium-induced depolymerization of tubulin and thus blocks the progression of mitosis (1). It is clinically applied for the treatment of ovarian, breast, stomach and non-small cell lung cancer (2, 3). When used clinically, it causes severe side-effects such as leucopenia. thrombocytopenia, neutropenia and fatigue (4) and anorexia and constipation (5). Patients who received platinum treatment with a taxane were more likely to experience grade 2 to 4 neuropathy (6). Paclitaxel has been reported to induce oxidative stress in liver (slight, but no significant decrease in glutathione in liver) (7). Considering many beneficial effects of antioxidants under optimal conditions (usually achieved by adopting lower doses that stimulate growth) (8, 9), prevention of chemotherapeutic drug-induced neurotoxicity by antioxidants has been actively studied in recent years (10,11).In order to search for substances that reduce neurotoxicity induced by paclitaxel, we first investigated whether nerve growth factor (NGF)-induced differentiating rat neuronal cells (used as neuron model) are also very sensitive to paclitaxel, like malignant cells. The possible protective activity of four antioxidants, docosahexaenoic acid (DHA), acetyl-L-carnitine hydrochloride (ALC), N-acetyl-L-cysteine (NAC) and sodium ascorbate, against neurotoxicity of paclitaxel was then investigated. 745

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“…CsA was administered orally at a dose of 10 mg/kg to patients 30 minutes before oral intake of Genetaxyl. The dosages were selected based on prior data suggesting that systemic paclitaxel exposure did not increase as the oral dose was increased from 180 to 540 mg/m 2 [17], and that systemic exposure to paclitaxel was not further affected by doses of CsA above 10 mg/kg [24]. For i.v.…”

Section: Paclitaxel Administrationmentioning

confidence: 99%

Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

et al. 2008

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The formulation excipient Cremophor EL (CrEL) is known to limit absorption of oral paclitaxel given together with cyclosporin A (CsA). We hypothesized that the use of oral Genetaxyl, a paclitaxel formulation containing only 20% CrEL would have an improved oral bioavailability. Cohorts of 6 patients were treated with oral Genetaxyl at a dose of 60, 120, or 180 mg/m 2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (175 mg/m 2 , 3-hour infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175 mg/m 2 , 3-hour infusion). The median area under the plasma concentration-time curve (AUC) and peak concentration of total paclitaxel following i.v. Genetaxyl were lower than those for i.v. Genaxol, as a result of significantly increased clearance (P = 0.017), and the AUC ratio for unbound to total paclitaxel for i.v. Genetaxyl was about 2 times higher than that for i.v. Genaxol (P = 0.0077). After oral administration of Genetaxyl at doses of 60, 120, and 180 mg/m 2 , the median total paclitaxel AUCs were 1.29, 1.60, and 1.85 µg×h/mL, respectively, suggesting a less than proportional increase in systemic exposure with increasing doses. The corresponding median values for the apparent bioavailability of oral Genetaxyl were similar when calculated either based on data for total paclitaxel (30.1%) or unbound paclitaxel (30.6%) when compared to i.v. Genetaxyl.

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The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel

Cited by 26 publications

References 25 publications

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Partial Protection of Paclitaxel-induced Neurotoxicity by Antioxidants

Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

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