Modulation of the tumor vasculature and oxygenation to improve therapy

Siemann, Dietmar W.; Horsman, Michael R.

doi:10.1016/j.pharmthera.2015.06.006

Cited by 126 publications

(114 citation statements)

References 215 publications

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“…Hypoxic conditions are seen in solid tumors despite hypervascularization due to an imbalance between the rates of tumor cell proliferation, new endothelial cell formation, and disorganized vascular supply [4,5]. Hypoxia has been shown to affect the L-arginine metabolic pathway in various types of cells, including smooth muscle cells and endothelial cells [6,7].…”

Section: Introductionmentioning

confidence: 99%

Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

Setty

Jin

Houghton

et al. 2016

Cell Physiol Biochem

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Background/Aims: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. Methods: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O₂, 5% CO₂) cellular proliferation. Results: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O₂, 5% CO₂). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. Conclusions: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma.

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Section: Introductionmentioning

confidence: 99%

Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

Setty

Jin

Houghton

et al. 2016

Cell Physiol Biochem

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“…There may be a lot of possible mechanisms accountable for this effect. One of the most important explanation is "Normalization of tumor vasculature", the VEGF Trap and BEV can improve the tumor microenvironment of interstitial hypertension, hypoxia and acidosis, leading to more efficient delivery of TMZ and oxygen to tumor cells 14,15 . A second possible mechanism is that by reducing vascular permeability, the VEGF Trap and BEV can prevent many serum-derived growth factors that promote tumor cell survival from reaching the tumor parenchyma, thus slowing down tumor cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, a large number of studies have shown that the efficacy of anti-angiogenic therapy alone was limited and the better therapeutic effects could be achieved in association with chemotherapy. This may be due to that the anti-angiogenic drugs can reestablish the tumor vasculature, normalize the tumor vessels and improve the delivery of drugs within the tumor 14,15 . Thus, we also combined AAV2-VEGF-Trap with TMZ to explore the antitumor effects and determine whether there is a synergistic effect.…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap: a new treatment option for glioma

Zhao

Zhang

Wang

et al. 2018

Cancer Biology & Therapy

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Background: Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap (AAV2-VEGF-Trap) has been reported to inhibit the growth of primary tumor as well as distant metastasis in 4T1 metastatic breast cancer models. The aim of this study was to investigate the inhibiting efficacy of AAV2-VEGF-Trap for glioma. Methods: The intracranial transplanted model of glioma in rats was established. They were treated with AAV2-VEGF-Trap, bevacizumab (BEV), temozolomide (TMZ), TMZ combined with AAV2-VEGF-Trap, TMZ combined with BEV and the control group, respectively. A 7.0 Tesla magnetic resonance (MR) was used to assess the tumor volumes and obtain the apparent diffusion coefficient (ADC) values. Immunohistochemical and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to evaluate the effects on tumor angiogenesis, proliferation and apoptosis. Results: The combination of TMZ with AAV2-VEGF-Trap or BEV showed greater tumor growth inhibition than the other groups, and the ADC values in these two groups were larger than that of the control group. The decreased microvessel density in treatment groups which contain AAV2-VEGF-Trap or BEV was observed. The reduced proliferation activity in groups containing TMZ and increased apoptotic tumor cells in TMZ combined with AAV2-VEGF-Trap group and TMZ combined with BEV group were detected. In addition, there were no differences in antitumor effect, ADC values, Ki-67 and CD31 staining and apoptosis analysis between the two combined therapy groups. Conclusion: AAV2-VEGF-Trap has an obvious anti-angiogenic effect and inhibits the growth of glioma just by a single intravenous injection, which is similar to BEV. Moreover, there is a synergistic antitumor effect between AAV2-VEGF-Trap and TMZ.

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“…Moreover, significant differences exist between physiological vessels and vessels in the tumor microenvironment. 9 The normal vasculature is a wellorganized network that is strictly controlled by a balance between proangiogenic and antiangiogenic factors and is arranged in a hierarchy of well-differentiated arteries, arterioles, capillaries, venules, and veins. In contrast, the overexpression of proangiogenic factors in the tumor environment results in an unevenly distributed and chaotic vasculature with irregular branches and the formation of arteriovenous shunts.…”

Section: Vascular Disrupting Agents (Vdas)mentioning

confidence: 99%

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

et al. 2016

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The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

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Modulation of the tumor vasculature and oxygenation to improve therapy

Cited by 126 publications

References 215 publications

Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap: a new treatment option for glioma

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

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