Abstract
Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.
Highlights
Solid tumor growth beyond about 1-3 mm in diameter depends extensively on angiogenesis initiating neovasculature for the supply of nutrients and oxygen [1]
In the late 19700 s, Pettit and co-workers discovered the combretastatins in the South African bush willow tree, Combretum caffrum, of which
There are distinct limitations, though many are readily overcome: (i) requires transfected cells to express luciferase effectively; (ii) requires administration of luciferin substrate; (iii) requires optical imaging system; (iv) typically limited to mice due to light scattering by tissues, Bioluminescence Imaging (BLI) has been reported in rats including prostate [198], brain [178,213] and lung tumors [214]
Summary
Solid tumor growth beyond about 1-3 mm in diameter depends extensively on angiogenesis initiating neovasculature for the supply of nutrients and oxygen [1]. Two types of therapy have been proposed to target tumor-associated vasculature: angiogenesis inhibiting agents (AIAs) inhibit the development of blood vessels a priori [9], while vascular disrupting agents (VDAs) target existing neovasculature [4,5,10,11]. VDA activity results from initiates microtubule disruption in characterized by profound cytoskeletal and morphological changes [16,17]. Activated endothelial cells, which initiates a signaling pathway characterized by profound endothelial cells up, leading to enhanced vascular leakage, and detachment cytoskeletal andround morphological changes [16,17]. As a biomarker, has been incorporated into relatively few clinical trials and the potential value and shortcomings were discussed extensively by O’Connor et al, regarding the parameters measurable by DCE-MRI [24]
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