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. 2008 Jan-Feb;84(1):128-37.
doi: 10.1111/j.1751-1097.2007.00208.x.

Combination therapy with antiangiogenic treatment and photodynamic therapy for the nude mouse bearing U87 glioblastoma

Feng Jiang  1 , Xuepeng Zhang, Steven N Kalkanis, Zhenggang Zhang, Hongyan Yang, Mark Katakowski, Xin Hong, Xuguang Zheng, Zhenping Zhu, Michael Chopp
Affiliations

"VSports在线直播" Combination therapy with antiangiogenic treatment and photodynamic therapy for the nude mouse bearing U87 glioblastoma

Feng Jiang (V体育2025版) et al. Photochem Photobiol. 2008 Jan-Feb.

Abstract

The objective of this study was to evaluate the effects of combination therapy with photodynamic therapy (PDT) and a novel antiangiogenic regimen using monoclonal antibodies against both vascular endothelial growth factor receptors (VEGFR)-1 (MF1) and VEGFR-2 (DC101) on intracranial glioblastoma xenografts in nude mice. Nude mice bearing intracerebral U87 glioblastoma were treated with PDT and the antiangiogenic regimen (MF1 and DC101) either alone or in combination, while those left untreated served as tumor controls. Tumor volume and animal survival time were analyzed to evaluate the outcome of different treatment modalities. In addition, the immunohistochemical expression of VEGF in the brain adjacent to the tumor, von Willebrand factor (vWF), apoptotic, and proliferative markers in the tumor area were examined. PDT or MF1 + DC101 alone significantly reduced the tumor volume and prolonged the survival time of glioma-implanted animals VSports手机版. Combined therapy markedly reduced tumor volume and increased survival time with significantly better outcomes than both monotherapies. Both vWF and VEGF levels significantly increased after PDT while they both significantly decreased after antiangiogenic treatment, compared with no treatment. PDT plus antiangiogenic treatment led to significant decreases in both vWF and VEGF expression, compared with PDT alone. Either PDT or antiangiogenic treatment alone significantly increased tumor cell apoptosis compared with no treatment, while combination therapy resulted in further augmentation of apoptosis. Antiangiogenic treatment with or without PDT significantly decreased tumor cell proliferation, compared with either no treatment or PDT alone. In summary, we demonstrate both significant inhibition of tumor growth and extended survival of mice treated by the combination therapy with PDT and antiangiogenic agents, compared with each single treatment, suggesting that the combination therapy may be a promising strategy to improve clinical outcomes in glioblastoma. .

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Figures

Figure 1
Figure 1
Schematic diagram of a coronal section with four fields selected from the brain adjacent to tumor (1-4) for semi-quantitative measurements of vascular endothelial growth factor expression and three fields selected within the tumor region (a-c) for semi-quantitative measurements of von Willebrand factor, Ki67 and TUNEL immuno-reactivity.
Figure 2
Figure 2
Representative H&E-stained images under 8× magnification collected at the cross section encompassing the largest tumor area in the brain of untreated tumor-bearing mice (a), mice with glioblastoma receiving MF1 + DC101 treatment (b), mice bearing tumor xenografts treated with photodynamic therapy (PDT) alone (c) and those undergoing antiangiogenic drugs plus PDT (d), killed on day 21 after tumor implantation. Black arrows outline the edge of the tumor mass. Scale bar = 500 μm.
Figure 3
Figure 3
Measurement of tumor volume. The tumor volume was significantly reduced after treatments by antiangiogenic regimen alone, photodynamic therapy (PDT) alone and combination therapy with antiangiogenic agents and PDT. Antiangiogenic drugs plus PDT further reduced the tumor volume, compared with each single-modality treatment. MF1 (400 μg) and DC101 (800 μg) were administered i.p. every other day from day 8 to day 14 after tumor implantation. PDT (Photofrin®: 2 mg kg-1; optical: 80 J cm-2) was conducted on day 7 after tumor implantation.
Figure 4
Figure 4
Kaplan-Meier survival plot. MF1 + DC101 treatment (P < 0.01) or photodynamic therapy (PDT) alone (P < 0.01) significantly prolonged the survival time of nude mice bearing U87 glioblastoma compared with no treatment. A significant increase in survival time was observed after combination therapy with PDT and antiangiogenic treatment compared with either monotherapy (P < 0.01 vs MF1 + DC101; P < 0.01 vs PDT). Ten animals in each group were analyzed.
Figure 5
Figure 5
Representative images of von Willebrand factor (vWF) immunohistochemistry. vWF is a marker for endothelial cells. vWF-stained small thin-walled vessels were shown under 200× magnification collected from the tumor area of nude mice bearing glioblastoma with no treatment (a), antiangiogenic treatment alone (b), photodynamic therapy (PDT) alone (c), or antiangiogenic treatment plus PDT (d). Black arrowheads indicate examples of small vessels with positive vWF immunostaining. Bar = 100 μm.
Figure 6
Figure 6
Semi-quantitative measurement of von Willebrand factor (vWF) expression in the tumor area. Both the number of vWF-positive vessels (a) and the total perimeter of vessels (b) in the tumor area were calculated. MF1 + DC101 with and without photodynamic therapy (PDT) significantly decreased vWF expression compared with no treatment. A significant increase in vWF expression was found after PDT-alone treatment compared with no treatment. PDT combined with antiangiogenic drugs resulted in a significant decrease in vWF immunoreactivity compared with PDT-alone treatment.
Figure 7
Figure 7
Representative vascular endothelial growth factor (VEGF) immunostained images under 400× magnification collected from the brain adjacent to tumor of the tumor-bearing brain without any treatment (a), after antiangiogenesis treatment (b), photodynamic therapy (PDT)-alone treatment (c), and antiangiogenic treatment combined with PDT (d), respectively. Black arrowheads indicate examples of sites with positive VEGF labeling. Bar = 50 μm.
Figure 8
Figure 8
Semi-quantitative measurement of vascular endothelial growth factor (VEGF) expression in the brain adjacent to tumor (BAT). MF1 + DC101 significantly decreased VEGF expression compared with the control group. A significant increase in VEGF expression in the BAT was found after photodynamic therapy (PDT) with or without antiangiogenesis treatment, compared with untreated tumor controls. PDT combined with antiangiogenic drugs significantly decreased VEGF immunoreactivity compared with PDT-alone treatment.
Figure 9
Figure 9
Representative images after TUNEL and hematoxylin counterstaining under 200× magnification, collected from the tumor region of control animals (a), animals with antiangiogenesis treatment (b), those treated with photodynamic therapy (PDT) alone (c) or those subjected to antiangiogenic drugs combined with PDT (d). Arrowheads indicate examples of TUNEL-positive cells. Bar = 100 μm.
Figure 10
Figure 10
Semi-quantitative measurement of TUNEL immunoreactivity in the tumor area. TUNEL was used to identify apoptotic cells. All of the three treatment strategies resulted in significant increases in tumor cell apoptosis, compared with no treatment. Combination therapy with antiangiogenic agents and photodynamic therapy (PDT) significantly increased the rate of tumor cell apoptosis compared with either antiangiogenic treatment alone or PDT alone.
Figure 11
Figure 11
Representative Ki67 immunostained images under 400× magnification collected from the tumor region of glioblastoma-bearing mice with no treatment (a), antiangiogenesis treatment alone (b), photodynamic therapy (PDT) alone (c) or antiangiogenic treatment plus PDT (d). Dark brown cells are Ki67-positive cells. Bar = 50 μm.
Figure 12
Figure 12
Semi-quantitative measurement of Ki67 expression in the tumor region. Ki67 is a robust marker of proliferative cells. Photodynamic therapy (PDT) alone did not affect tumor cell proliferation. MF1 + DC101 with or without PDT resulted in a significant decrease in Ki67 expression in the tumor area compared with either no treatment or PDT alone.
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