Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer

Richly, Heike; Kupsch, P.; Passage, K; Grubert, M.; Ra, Hilger; Voigtmann, R.; Schwartz, Brian; Brendel, E.; Christensen, Ole; Cg, Haase; Strumberg, Dirk

doi:10.5414/cpp42650

Cited by 50 publications

(31 citation statements)

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“…A case in point is sorafenib where clinical trials show that this agent can be effective in renal cell cancer patients with few minor clinically manageable side effects extending life by f12 weeks (16, 17, 35, 39, 41 -44). However, sorafenib is less effective for treating other types of cancer, including melanoma and breast cancer, which is driving the search for agents that can be combined with sorafenib to enhance its clinical efficacy (16,35,39,41,43,44).…”

Section: Discussionmentioning

confidence: 99%

Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development

Tran¹,

Smith

Kester³

et al. 2008

Clinical Cancer Research

117

109

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Purpose: Deregulation of phosphatidylinositol 3-kinase/Akt and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathways occurs in melanoma and breast cancer, deregulating normal cellular apoptosis and proliferation. Therapeutic cocktails simultaneously targeting these pathways could promote synergistically acting tumor inhibition. However, agents with manageable toxicity and mechanistic basis for synergy need identification. The purpose of this study is to evaluate the preclinical therapeutic efficacy and associated toxicity of combining sorafenib with nanoliposomal ceramide. Experimental Design: Effects of sorafenib and nanoliposomal ceramide as single and combinatorial agents were examined on cultured cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assays and CalcuSyn software used to assess synergistic or additive inhibition. Western blotting measured cooperative effects on signaling pathways. Rates of proliferation, apoptosis, and angiogenesis were measured in sizeand time-matched tumors to identify mechanistic basis for inhibition. Toxicity was evaluated measuring animal weight, blood toxicity parameters, and changes in liver histology. Results: Sorafenib and nanoliposomal ceramide synergistically inhibited cultured cells by cooperatively targeting mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling. A1-to 2-fold increase in cellular apoptosis and 3-to 4-fold decrease in cellular proliferation were observed following combination treatment compared with single agents, which caused synergistically acting inhibition. In vivo, an f30% increase in tumor inhibition compared with sorafenib treatment alone and an f58% reduction in tumor size compared with nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity. Conclusions: This study shows that nanoliposomal ceramide enhances effectiveness of sorafenib causing synergistic inhibition. Thus, a foundation is established for clinical trials evaluating the efficacy of combining sorafenib with nanoliposomal ceramide for treatment of cancers.

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Section: Discussionmentioning

confidence: 99%

Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development

Tran¹,

Smith

Kester³

et al. 2008

Clinical Cancer Research

117

109

View full text Add to dashboard Cite

show abstract

“…Sorafenib was selected as a reference standard, because it has been extensively used in clinical trials for melanoma. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Regarding the terminal substituents on the phenyl ring of the tail, it was found that compounds Ih, IIf, IIg, and IIh having amide moiety were more potent than compounds Ib, IIa, IIb, and IIc having urea moiety. As to the substituents on the chlorophenyl ring, compounds IIb, IId, IIe, IIf, IIg, and IIh with hydroxyl group showed higher antiproliferative activity in comparison with the corresponding methoxy derivatives Ib, Id, Ie, Ig, Ih, and Ii.…”

Section: Resultsmentioning

confidence: 99%

“…[4][5][6] Recently, Sorafenib, as well as other diarylureas, have been evaluated as potent and selective antiproliferative agents for the treatment of melanoma. [7][8][9][10][11][12] The promising results have encouraged many research groups to investigate diarylurea scaffolds to develop new derivatives for the treatment of cancer. [13][14][15][16][17] Accordingly, we have synthesized a new series of diaryl ureas, and reported their antiproliferative activity against A375 human melanoma cell line.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activities of 1-Substituted-3-(3-chloro-5-methoxyphenyl)-4-pyridinylpyrazole Derivatives Against Melanoma Cell Line

Choi¹,

Oh²

2009

Bulletin of the Korean Chemical Society

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The synthesis of a new series of diarylureas and amides having a 1-substituted-3-(3-chloro-5-methoxyphenyl)-4-pyridinylpyrazole scaffold is reported here. The in vitro antiproliferative activities of these diaryl derivatives against human melanoma cell line A375 were tested and the effect of substituents on the phenyl ring was investigated. Most of the newly synthesized compounds generally showed superior or similiar activity against A375 to Sorafenib. Among these compounds, IId, IIg and IIh showed excellent activity against A375 compared to Sorafenib.

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“…Sorafenib [10][11][12][13][14][15] is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. 16 It inhibits Raf kinases (Raf-1 and b-Raf), as well as proangiogenic receptor tyrosine kinases of the PDGFR and VEGFR family.…”

Section: -6mentioning

confidence: 99%

Design and Synthesis of 3-(3-Chloro-4-substituted phenyl)-4-(pyridin-4-yl)-1Hpyrazole- 1-carboxamide Derivatives and Their Antiproliferative Activity Against Melanoma Cell Line

El‐Gamal¹,

Oh²

2011

Bulletin of the Korean Chemical Society

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Design and synthesis of new 3,4-diarylpyrazole-1-carboxamide derivatives are described. Their antiproliferative activity against A375 human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The pharmacological results indicated that most of the synthesized compounds showed moderate activity against A375, compared with Sorafenib. On the other hand, compounds Ia, Ie, IIb, and IIh were more potent than Sorafenib. In addition, compound IIa was equipotent to Sorafenib. Among all of these derivatives, compound IIb which has diethylamino and phenolic moieties showed the most potent antiproliferative activity against A375 human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIb into the domain of V600E-b-Raf and the binding mode was studied.

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Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer

Cited by 50 publications

References 0 publications

Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development

Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development

Synthesis and Antiproliferative Activities of 1-Substituted-3-(3-chloro-5-methoxyphenyl)-4-pyridinylpyrazole Derivatives Against Melanoma Cell Line

Design and Synthesis of 3-(3-Chloro-4-substituted phenyl)-4-(pyridin-4-yl)-1Hpyrazole- 1-carboxamide Derivatives and Their Antiproliferative Activity Against Melanoma Cell Line

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