Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A.

Abstract

The impact of antiangiogenic therapy on the Sp1/vascular endothelial growth factor (VEGF) pathway and that of alteration of Sp1 signaling on the efficacy of antiangiogenic therapy is unclear, yet understanding their interactions has significant clinical implications. Treatment with bevacizumab, a neutralizing antibody against VEGF, suppressed human pancreatic cancer growth in nude mice. Gene expression analyses revealed that this treatment substantially up-regulated the expression of Sp1 and its downstream target genes, including VEGF and epidermal growth factor receptor, in tumor tissues, whereas it did not have this effect on pancreatic cancer cells in culture. Treatment with mithramycin A, an Sp1 inhibitor, suppressed the expression of Sp1 and its downstream target genes in both cell culture and tumors growing in nude mice. Combined treatment with bevacizumab and mithramycin A produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Thus, treatment with bevacizumab may block VEGF function but activate the pathway of its expression via positive feedback. Given the fact that Sp1 is an important regulator of the expression of multiple angiogenic factors, bevacizumab-initiated up-regulation of Sp1 and subsequent overexpression of its downstream target genes may profoundly affect the potential angiogenic phenotype and effectiveness of antiangiogenic strategies for human pancreatic cancer. Therefore, this study is the first to show the significance and clinical implications of alteration of Sp1 signaling in antiangiogenic therapy for pancreatic cancer and other cancers.

• Authors: Zhiliang Jia, Jun Zhang, Daoyan Wei, Liwei Wang, Ping Yuan, Xiangdong Le, Qiang Li, James Yao, Keping Xie
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 10 Pg. 4878-85 (May 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17510417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Sp1 Transcription Factor
• Vascular Endothelial Growth Factor A
• Bevacizumab
• mithramycin A
• Plicamycin

Topics

• Adenocarcinoma (blood supply, drug therapy, genetics, metabolism)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Bevacizumab
• Cell Line, Tumor
• Drug Synergism
• Female
• Gene Expression (drug effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (drug therapy, genetics, metabolism)
• Pancreatic Neoplasms (blood supply, drug therapy, genetics, metabolism)
• Plicamycin (analogs & derivatives, pharmacology)
• Promoter Regions, Genetic
• Sp1 Transcription Factor (biosynthesis, genetics, metabolism)
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)
• Xenograft Model Antitumor Assays