Implications of Increase in Vascular Permeability in Tumors by VEGF: A Commentary on the Pioneering Work of Harold Dvorak

Dewhirst, Mark W.; Ashcraft, Kathleen A.

doi:10.1158/0008-5472.can-16-1292

Cited by 19 publications

(8 citation statements)

References 26 publications

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“…Tumour endothelial cells proliferate faster but form less tight junctions than endothelial cells in normal tissue 9 . Production of vascular endothelial growth factor (VEGF) by tumour cells is an important factor causing leaky endothelial cell junctions and hyperpermeability 25,26 . Tumour blood vessels often show increased tortuosity.…”

Section: Drug Transport In the Circulationmentioning

confidence: 99%

Transport of drugs from blood vessels to tumour tissue

2017

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The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

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Section: Drug Transport In the Circulationmentioning

confidence: 99%

Transport of drugs from blood vessels to tumour tissue

2017

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“…Several strategies have been applied to reduce tumor IFP, such as affecting the contractile function of fiber cells, directly reducing extracellular matrix, − and inhibiting ECM oversynthesis through some cancer-associated growth factors. ,,,, Imatinib (IMA, STI571) is a potent tyrosine kinase inhibitor and could inhibit the expression of Bcr-Abl gene and PDGF receptors as well . Previous reports have proven that IMA can inhibit the overproduction of ECM through inhibiting PDGFR-β and disrupting the “CAFs–ECM interaction”. , Thus, IMA could effectively reduce tumor IFP and improve the delivery efficiency of therapeutic drugs …”

Section: Introductionmentioning

confidence: 99%

Reducing Interstitial Fluid Pressure and Inhibiting Pulmonary Metastasis of Breast Cancer by Gelatin Modified Cationic Lipid Nanoparticles

Gao

Zhang

Huang

et al. 2017

ACS Appl. Mater. Interfaces

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Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue, and it constitutes a great obstacle for the delivery of antitumor drugs, thus becoming a potential target for cancer therapy. In this study, cationic nanostructured lipid carriers (NLCs) were modified by low molecular weight gelatin to achieve the desirable reduction of tumor IFP and improve the drug delivery. In this way, the chemotherapy of formulations on tumor proliferation and pulmonary metastasis was further improved. The nanoparticles were used to load three drugs, docetaxel (DTX), quercetin (Qu), and imatinib (IMA), with high encapsulation efficiency of 89.54%, 96.45%, and 60.13%, respectively. GNP-DTX/Qu/IMA nanoparticles exhibited an enzyme-sensitive drug release behavior, and the release rate could be mediated by matrix metalloproteinases (MMP-9). Cellular uptake and MTT assays showed that the obtained GNP-DTX/Qu/IMA could be internalized into human breast 4T1 cells effectively and exhibited the strongest cytotoxicity. Moreover, GNP-DTX/Qu/IMA demonstrated obvious advantages in inducing apoptosis and mediating the expression of apoptosis-related proteins (Caspase 3, Caspase 9, and bcl-2). In the wound-healing assay, GNP-DTX/Qu/IMA exhibited evidently inhibition of cell migration. The benefits of tumor IFP reduction induced by GNP-DTX/Qu/IMA were further proved after a continuous administration to 4T1 tumor-bearing mice. Finally, in the in vivo antitumor assays, GNP-DTX/Qu/IMA displayed stronger antitumor efficiency as well as suppression on pulmonary metastasis. In conclusion, the GNP-DTX/Qu/IMA system might be a promising strategy for metastatic breast cancer treatment.

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“…2,3 The prominent role of VEGFA in developmental vascular growth is underscored by severe defects leading to embryonic lethality caused by the loss of a single allele of VEGFA. 4 Successful targeting of VEGFA with neutralizing antibodies is generally viewed as revolutionary and a turning point in antiangiogenic therapy.…”

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confidence: 99%