Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

Oostendorp, Roos L.; Huitema, Alwin D. R.; Rosing, Hilde; Jansen, Robert S.; Heine, Rob ter; Keessen, Marianne; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1158/1078-0432.ccr-08-2944

Cited by 64 publications

(66 citation statements)

References 24 publications

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“…The heat map of Bliss scores for IGROV-1 (Fig. 1C) shows that there are greater than additive effects across a clinically relevant range of doses for both compounds (11,17). In contrast, the TOV21G cell line exhibited minimal synergy across a small dose range.…”

Section: Resultsmentioning

confidence: 97%

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Wong¹,

Tan²,

Zha³

et al. 2012

Molecular Cancer Therapeutics

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To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-x L seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-x L would enrich for patients responsive to the combination. We evaluated Bcl-x L levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-x L were less sensitive to taxane treatment (10 of 12) Bcl-x L positive patients, P ¼ 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-x L .

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Section: Resultsmentioning

confidence: 97%

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Wong¹,

Tan²,

Zha³

et al. 2012

Molecular Cancer Therapeutics

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“…After 24 hours, cells were treated with navitoclax (dose range ¼ 0.12-3.3 mmol/L) and paclitaxel or DTX (dose range ¼ 3-100 nmol/L) in a 5 Â 5 matrix of concentrations chosen to encompass clinically relevant doses (23,24). Each treatment was done in quadruplicate.…”

Section: Cell Viability Assay and Western Blottingmentioning

confidence: 99%

Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models

Tan¹,

Malek²,

Zha³

et al. 2011

Clinical Cancer Research

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Purpose: To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non-small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.Experimental Design: We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-x L , and Bcl-w (1), and evaluated synergy. We next used timelapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-x L in NSCLC tumor tissues.Results: All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-x L and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-x L will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-x L levels.Conclusions: The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-x L .

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“…14,15 Several studies have shown that the oral bioavailability of docetaxel can be enhanced significantly by coadministration of Pgp and/or CYP3A inhibitors, such as cyclosporin A, ritonavir, interferon-alpha, and ontogen (ONT-093). 14,[16][17][18] However, the usefulness of these drugs in clinical practice is limited, especially for repeated administration, because of the risk of side effects, which include immunosuppression. 19 Solid lipid nanoparticles (SLNs) are submicron (50-1,000 nm) colloidal particulate systems composed of physiologically tolerable lipid components, which remain in the solid state at room temperature.…”

Section: Introductionmentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

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Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

Cited by 64 publications

References 24 publications

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

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