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Sorafenib for the treatment of unresectable hepatocellular carcinoma.

Furuse J - Biologics (2008)

Bottom Line: Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta).Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments.The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Medical Oncology, School of Medicine, Kyorin University.

ABSTRACT
Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.

No MeSH data available.


Related in: MedlinePlus

Mechanism of action of sorafenib. Sorafenib exerts a dual anticancer effect on the tumor and tumor vasculature by inhibiting Raf kinases including Raf-1 as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), etc. Reproduced with permission from Gollob JA, Wilhelm S, Carter C, et al 2006. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33:392–406. Copyright © 2006 Elsevier.Abbreviation: Sf, sorafenib.
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f2-btt-2-779: Mechanism of action of sorafenib. Sorafenib exerts a dual anticancer effect on the tumor and tumor vasculature by inhibiting Raf kinases including Raf-1 as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), etc. Reproduced with permission from Gollob JA, Wilhelm S, Carter C, et al 2006. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33:392–406. Copyright © 2006 Elsevier.Abbreviation: Sf, sorafenib.

Mentions: The anti-tumor efficacy and mechanism of action of sorafenib was investigated in vitro on PLC/PRF/5 and HepG2 HCC cells and in vivo on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice (Liu et al 2006). Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Furthermore, sorafenib reduced the phosphorylation level of eIF4E and down-regulated the anti-apoptotic protein Mcl-1 in a MEK/ERK-independent manner. Sorafenib demonstrated dose-dependent tumor growth inhibition of implanted PLC/PRF/5 tumor xenografts (Liu et al 2006). The in vivo anti-tumor activity of sorafenib correlated with the inhibition of MAPK signaling, which is indicative of Raf kinase inhibition, and inhibition of tumor microvessel area as measured by the reduction in CD34 staining (Liu et al 2006). These experiments showed that the anti-tumor activity of sorafenib was attributed to inhibition of tumor angiogenesis of VEGFR and PDGFR and direct effects on tumor cell proliferation/survival of Raf kinase signaling-dependent and signaling-independent mechanisms (Figure 2).


Sorafenib for the treatment of unresectable hepatocellular carcinoma.

Furuse J - Biologics (2008)

Mechanism of action of sorafenib. Sorafenib exerts a dual anticancer effect on the tumor and tumor vasculature by inhibiting Raf kinases including Raf-1 as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), etc. Reproduced with permission from Gollob JA, Wilhelm S, Carter C, et al 2006. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33:392–406. Copyright © 2006 Elsevier.Abbreviation: Sf, sorafenib.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2727884&req=5

f2-btt-2-779: Mechanism of action of sorafenib. Sorafenib exerts a dual anticancer effect on the tumor and tumor vasculature by inhibiting Raf kinases including Raf-1 as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), etc. Reproduced with permission from Gollob JA, Wilhelm S, Carter C, et al 2006. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33:392–406. Copyright © 2006 Elsevier.Abbreviation: Sf, sorafenib.
Mentions: The anti-tumor efficacy and mechanism of action of sorafenib was investigated in vitro on PLC/PRF/5 and HepG2 HCC cells and in vivo on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice (Liu et al 2006). Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Furthermore, sorafenib reduced the phosphorylation level of eIF4E and down-regulated the anti-apoptotic protein Mcl-1 in a MEK/ERK-independent manner. Sorafenib demonstrated dose-dependent tumor growth inhibition of implanted PLC/PRF/5 tumor xenografts (Liu et al 2006). The in vivo anti-tumor activity of sorafenib correlated with the inhibition of MAPK signaling, which is indicative of Raf kinase inhibition, and inhibition of tumor microvessel area as measured by the reduction in CD34 staining (Liu et al 2006). These experiments showed that the anti-tumor activity of sorafenib was attributed to inhibition of tumor angiogenesis of VEGFR and PDGFR and direct effects on tumor cell proliferation/survival of Raf kinase signaling-dependent and signaling-independent mechanisms (Figure 2).

Bottom Line: Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta).Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments.The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Medical Oncology, School of Medicine, Kyorin University.

ABSTRACT
Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.

No MeSH data available.


Related in: MedlinePlus