Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Research Article

Evaluation of Local Injection of Bevacizumab against Triple-Negative Breast Cancer Xenograft Tumors

Author(s): Xin Jiang, Qiao-Li Zhang, Tie-Gang Liu, Wei-Peng Zhao, Ming Yang, Li-Na Wang, Wei-Liang Sun, Lin Pan, Ai-Ping Luo, Jin-Chang Huang* and Xiao-Hong Gu*

Volume 25, Issue 8, 2019

Page: [862 - 870] Pages: 9

DOI: 10.2174/1381612825666190306164157

Price: $65

Abstract

Background and objective: Bevacizumab (BVZ) is a recombinant humanized antibody that inhibits the vascular endothelial growth factor A (VEGFA) and is used for the treatment of various types of cancer. BVZ is primarily given by the intravenous drip (I.V.), which often leads to low efficacy and various side effects. Therefore, the present study was to evaluate the effect of local delivery of BVZ against triple-negative breast cancer (TNBC) xenograft tumors.

Methods: Mice 4T1 TNBC cells were engrafted in female BALB/c mice. After the tumors reached about 5 mm (diameter), animals were treated with BVZ through the local injection from four directions around the tumors. The tumor growth, survival and potential mechanisms of action were evaluated.

Results: The growth and microvessel density of engrafted tumors were dramatically reduced with the tumor inhibition rate of 32.8 ± 3%. No obvious side effects were observed. The expression of VEGFA, VEGF receptor (VEGFR), matrix metalloproteinase (MMP)-2, MMP-9, Delta-like ligand 4 (DLL4) and Integrin-5 was significantly reduced in TNBC tumor tissues. In contrast, tissue inhibitor of matrix metalloproteinase (TIMP)-2 was significantly upregulated in xenograft tumors. Additionally, local delivery of BVZ led to the reduction of VEGFA and tumor necrosis factor (TNF)-alpha in the serum. Protein-protein interaction (PPI) analysis revealed that the proteins altered by the local delivery of BVZ were associated with angiogenesis and regulation of cell migration.

Conclusion: This study provided evidence associated with local delivery of BVZ against TNBC tumors supporting the use of BVZ local injections to overcome some of the disadvantages associated with I.V. therapy with BVZ.

Keywords: Triple-negative breast cancer, bevacizumab, local delivery, vascular endothelial growth factor A (VEGFA), matrix metalloproteinase, I.V. therapy.

[1]
Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global Cancer in Women: Burden and Trends. Cancer Epidemiol Biomarkers Prev 2017; 26: 444-57.
[2]
Yu L, Li K, Zhang X. Next-generation metabolomics in lung cancer diagnosis, treatment and precision medicine: mini review. Oncotarget 2017; 8: 115774-86.
[3]
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67: 439-48.
[4]
Fremd C, Jaeger D, Schneeweiss A. Targeted and immuno-biology driven treatment strategies for triple-negative breast cancer: current knowledge and future perspectives. Expert Rev Anticancer Ther 2018; 1-14.
[5]
Agostini D, Natalucci V, Baldelli G, et al. New Insights into the Role of Exercise in Inhibiting mTOR Signaling in Triple-Negative Breast Cancer. Oxid Med Cell Longev 2018; 2018: 5896786.
[6]
Viallard C, Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 2017; 20: 409-26.
[7]
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307.
[8]
Foekens JA, Peters HA, Grebenchtchikov N, et al. High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 2001; 61: 5407-14.
[9]
Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14: 933-42.
[10]
Bianchi-Smiraglia A, Paesante S, Bakin AV. Integrin beta5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways. Oncogene 2013; 32: 3049-58.
[11]
Cathcart J, Pulkoski-Gross A, Cao J. Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. Genes Dis 2015; 2: 26-34.
[12]
Mehner C, Hockla A, Miller E, Ran S, Radisky DC, Radisky ES. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget 2014; 5: 2736-49.
[13]
Liu Z, Fan F, Wang A, Zheng S, Lu Y. Dll4-Notch signaling in regulation of tumor angiogenesis. J Cancer Res Clin Oncol 2014; 140: 525-36.
[14]
Di Mauro C, Rosa R, D’Amato V, et al. Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers. Br J Cancer 2017; 116: 1425-35.
[15]
Greenberg S, Rugo HS. Triple-negative breast cancer: role of antiangiogenic agents. Cancer J 2010; 16: 33-8.
[16]
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666-76.
[17]
Stevenson CE, Nagahashi M, Ramachandran S, Yamada A, Bear HD, Takabe K. Bevacizumab and breast cancer: what does the future hold? Future Oncol 2012; 8: 403-14.
[18]
Wolinsky JB, Colson YL, Grinstaff MW. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release 2012; 159: 14-26.
[19]
Han J, Xia Y, Lin L, Zhang Z, Tian H, Li K. Next-generation Metabolomics in the Development of New Antidepressants: Using Albiflorin as an Example. Curr Pharm Des 2018; 24: 2530-40.
[20]
Moses MA, Brem H, Langer R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell 2003; 4: 337-41.
[21]
Sagiv-Barfi I, Czerwinski DK, Levy S, et al. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med 2018; 10(426) pii: eaan 4488.
[22]
Yang F, Hu M, Lei Q, et al. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model. Cell Death Dis 2015; 6: e1701.
[23]
Pereira T, Dodal S, Tamgadge A, Bhalerao S, Tamgadge S. Quantitative evaluation of microvessel density using CD34 in clinical variants of ameloblastoma: An immunohistochemical study. J Oral Maxillofac Pathol 2016; 20: 51-8.
[24]
Kammerer U, Kapp M, Gassel AM, et al. A new rapid immunohistochemical staining technique using the EnVision antibody complex. J Histochem Cytochem 2001; 49: 623-30.
[25]
Rizzardi AE, Johnson AT, Vogel RI, et al. Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring. Diagn Pathol 2012; 7: 42.
[26]
DuPré SA, Redelman D, Hunter KW Jr. The mouse mammary carcinoma 4T1: characterization of the cellular landscape of primary tumours and metastatic tumour foci. Int J Exp Pathol 2007; 88(5): 351-60.
[27]
Isobe T, Uchino K, Makiyama C, et al. Analysis of adverse events of bevacizumab-containing systemic chemotherapy for metastatic colorectal cancer in Japan. Anticancer Res 2014; 34: 2035-40.
[28]
Mollard S, Ciccolini J, Imbs DC, El Cheikh R, Barbolosi D, Benzekry S. Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis. Oncotarget 2017; 8: 23087-98.
[29]
Alidzanovic L, Starlinger P, Schauer D, et al. The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance. Oncotarget 2016; 7: 57197-212.
[30]
Bagheri A, Soheili ZS, Ahmadieh H, et al. Simultaneous application of bevacizumab and anti-CTGF antibody effectively suppresses proangiogenic and profibrotic factors in human RPE cells. Mol Vis 2015; 21: 378-90.
[31]
Zhang M, Chu S, Zeng F, Xu H. Bevacizumab modulates the process of fibrosis in vitro. Clin Exp Ophthalmol 2015; 43: 173-9.
[32]
Tian Y, Jiang X, Zhao W, et al. Acupuncture enhances anticancer effects of cyclophosphamide on 4T1 tumors via suppression of angiogenesis in BALB/c mice. J Tradit Chin Med Sci 2017; 4: 5.
[33]
Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 2007; 67: 11244-53.
[34]
Noguera-Troise I, Daly C, Papadopoulos NJ, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006; 444: 1032-7.
[35]
Scehnet JS, Jiang W, Kumar SR, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 2007; 109: 4753-60.
[36]
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592-603.
[37]
Li JL, Sainson RC, Oon CE, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res 2011; 71: 6073-83.
[38]
Goukassian DA, Qin G, Dolan C, et al. Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization. Circulation 2007; 115: 752-62.
[39]
Yoshida S, Ono M, Shono T, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 1997; 17: 4015-23.
[40]
Cui GH, Chen WH, Xue KY, Liu F, Chen Y. Effects of triptolide and TNF-alpha on the expression of VEGF in Raji cells and on angiogenesis in ECV304 cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2006; 14: 1008-12.
[41]
Arimura N, Otsuka H, Yamakiri K, et al. Vitreous mediators after intravitreal bevacizumab or triamcinolone acetonide in eyes with proliferative diabetic retinopathy. Ophthalmology 2009; 116: 921-6.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy