title: Convection-enhanced delivery of sorafenib and suppression of tumor progression in a murine model of brain melanoma through the inhibition of signal transducer and activator of transcription 3.
abstract: OBJECT Despite recent advances, metastatic melanoma remains a terminal disease, in which life-threatening brain metastasis occurs in approximately half of patients. Sorafenib is a multikinase inhibitor that induces apoptosis of melanoma cells in vitro. However, systemic administration has been ineffective because adequate tissue concentrations cannot be achieved. This study investigated if convection-enhanced delivery (CED) of sorafenib would enhance tumor control and survival via inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in a murine model of metastatic brain melanoma. METHODS Melanoma cells treated with sorafenib in vitro were examined for signaling and survival changes. The effect of sorafenib given by CED was assessed by bioluminescent imaging and animal survival. RESULTS The results showed that sorafenib induced cell death in the 4 established melanoma cell lines and in 1 primary cultured melanoma cell line. Sorafenib inhibited Stat3 phosphorylation in HTB65, WYC1, and B16 cells. Accordingly, sorafenib treatment also decreased expression of Mcl-1 mRNA in melanoma cell lines. Because sorafenib targets multiple pathways, the present study demonstrated the contribution of the Stat3 pathway by showing that mouse embryonic fibroblast (MEF) Stat3 +/+ cells were significantly more sensitive to sorafenib than MEF Stat3 -/- cells. In the murine model of melanoma brain metastasis used in this study, CED of sorafenib increased survival by 150% in the treatment group compared with animals receiving the vehicle control (p < 0.01). CED of sorafenib also significantly abrogated tumor growth. CONCLUSIONS The data from this study indicate that local delivery of sorafenib effectively controls brain melanoma. These findings validate further investigation of the use of CED to distribute molecularly targeted agents.
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lin
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Li-Chen J
authors.initials: LC
authors.lastname: Hsu
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Brandon
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jandial
authors.affiliation: Faculty of Health Sciences, University of Macau, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, California; and.
authors.forename: Mike Y
authors.initials: MY
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D018481:Convection; D064593:Heterografts; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D000077157:Sorafenib; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib
keywords: B16-ffluc = firefly luciferase-expressing B16 melanoma cell line; CED = convection-enhanced delivery; DMSO = dimethyl sulfoxide; IC50 = median inhibitory concentration; IL-6 = interleukin 6; PBS = phosphate-buffered saline; Stat3; Stat3 = signal transducer and activator of transcription 3; brain; convection-enhanced delivery; melanoma; mice; oncology; pStat3 = phosphorylation of Stat3; sorafenib