|Title:||Robust combination of liver stereotactic body radiotherapy modulates pharmacokinetics of sorafenib toward preferable parameters||Authors:||Hsieh C.-H.
|Issue Date:||2020||Publisher:||Nature Research||Journal Volume:||10||Journal Issue:||1||Start page/Pages:||9575||Source:||Scientific Reports||Abstract:||
To evaluate the effect and mechanism of radiotherapy (RT)–sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT2Gy and RT9Gy groups and the sequential RT9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT2Gy group (p = 0.036). Sequential RT2Gy and RT9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens. ? 2020, The Author(s).
|ISSN:||2045-2322||DOI:||10.1038/s41598-020-66583-9||SDG/Keyword:||antineoplastic agent; cyclosporine; CYP3A4 protein, human; cytochrome P450 3A; cytochrome P450 3A inhibitor; immunoglobulin enhancer binding protein; protein kinase inhibitor; sorafenib; animal; complication; enzyme induction; germfree animal; hepatic portal vein; human; liver cell carcinoma; liver tumor; male; metabolism; multimodality cancer therapy; procedures; radiation response; radiosurgery; rat; retrospective study; Sprague Dawley rat; tissue distribution; tumor cell line; vein thrombosis; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Hepatocellular; Cell Line, Tumor; Combined Modality Therapy; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Radiation; Enzyme Induction; Humans; Liver Neoplasms; Male; NF-kappa B; Portal Vein; Protein Kinase Inhibitors; Radiosurgery; Rats; Rats, Sprague-Dawley; Retrospective Studies; Sorafenib; Specific Pathogen-Free Organisms; Tissue Distribution; Venous Thrombosis
|Appears in Collections:||物理治療學系所|
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