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The Anti-Tumor Effect of Nab-Paclitaxel Proven by Patient-Derived Organoids.

ABSTRACT: Background:Nab-paclitaxel has been widely used in treating breast cancer and pancreatic patients for its low toxicity and high efficiency. However, its role in gastric cancer (GC) remains ambiguous. The aim of our study was to test the anti-tumor activity of nab-paclitaxel using GC patient-derived organoids. Methods:By using the organoid culture system, we describe the establishment of human gastric cancer organoid lines from surgical samples of three patients with gastric cancer. The consistency of these organoids with original cancer tissues was evaluated by histopathological examination. The characteristics of the cancer organoids were tested using immunofluorescence (IF) staining. Using organoids, the anti-tumor efficiencies of nab-paclitaxel, 5-Fu and epirubicin were compared by CCK8 assay and Annexin V-FITC/PI staining. Results:Three organoids were successfully established and passaged. The morphology of the established GC organoids was consistent with original cancer tissues. The IC50 of nab-paclitaxel was 3.68 ?mol/L in hGCO1, 2.41 ?mol/L in hGCO2 and 2.91 ?mol/L in hGCO3, which was significantly lower than those of 5-FU (72.99 ?mol/L in hGCO1, 28.32 ?mol/L in hGCO2 and 2.91 ?mol/L in hGCO3) and epirubicin (25.85?mol/L in hGCO1, 15.15 ?mol/L in hGCO2 and 7.60 ?mol/L in hGCO3). When each organoid lines were treated with nab-paclitaxel for increasing period of time, the percentage of the apoptotic cells in each organoid increased accordingly. Conclusion:Nab-paclitaxel showed strong anti-tumor activity and had the potential to become front-line drug for treating GC patients. Gastric cancer organoid may be a good tool to predict in vivo response to drugs.

SUBMITTER: Xiao X

PROVIDER: S-EPMC7322144 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Anti-Tumor Effect of Nab-Paclitaxel Proven by Patient-Derived Organoids.

Xiao Xing X Chen Wei W Wei Zhe-Wei ZW Chu Wei-Wei WW Lu Xiao-Fang XF Li Bo B Chen Hong H Meng Si-Jun SJ Hao Teng-Fei TF Wei Ji-Tao JT He Yu-Long YL Zhang Chang-Hua CH

OncoTargets and therapy 20200624

<h4>Background</h4>Nab-paclitaxel has been widely used in treating breast cancer and pancreatic patients for its low toxicity and high efficiency. However, its role in gastric cancer (GC) remains ambiguous. The aim of our study was to test the anti-tumor activity of nab-paclitaxel using GC patient-derived organoids.<h4>Methods</h4>By using the organoid culture system, we describe the establishment of human gastric cancer organoid lines from surgical samples of three patients with gastric cancer. ...[more]

PMID: 32612367

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Project description:Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.

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The Anti-Tumor Effect of Nab-Paclitaxel Proven by Patient-Derived Organoids.

Publications

The Anti-Tumor Effect of Nab-Paclitaxel Proven by Patient-Derived Organoids.

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