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Vascular Disruptive Agents for the Treatment of Cancer

:	Tim Meyer
:	Tim Meyer
:	Vascular Disruptive Agents for the Treatment of Cancer
:	Springer-Verlag
:	9781441966094
:	1
:	CHF 132.90
:

:	Nichtklinische Fächer
:	English

:	256
:	Wasserzeichen
:	PC/MAC/eReader/Tablet
:	PDF

Angiogenesis (formation of new vessels from pre-existing ones) is a crucial early event in the process of tumor development. New vessels supply the tumor with nutrients that are needed for further local growth and enable distant metastases (Folkman 1995). Judah Folkman (1971) highlighted the potential therapeutic imp- cations of tumor angiogenesis. He hypothesized that if tumor angiogenesis is inhibited, then tumor growth and metastasis will be impaired greatly or even impossible. The subsequent quest for endogenous and exogenous inhibitors of angiogenesis has yielded a variety of promising therapeutic agents that block one or more angiogenic pathways, a few of which have been approved by the FDA (e. g. , bevacizumab, sorafenib, sunitinib) for use as single agents or in combination with chemotherapy in specific populations of cancer patients (Sessa et al. 2008). There has also been a dramatic expansion in the exploration of novel anti-angiogenic agents pre-clinically and in clinical trials (Ferrara 2002). Some of the most promising data comes from the development of agents that inhibit one of the key growth factors involved in tumor angiogenesis - vascular endothelial growth factor (VEGF) (Ferrara et al. 2003). Bevacizumab is a monoclonal antibody against VEGF that was the first an- angiogenic agent that improved significantly the overall survival of patients with colorectal and non-squamous non-small cell lung cancer (Ferrara et al. 2005). Various agents that target tumor angiogenesis are currently under investigation in different cancer types in many clinical trials (Ferrara and Kerbel 2005).

Dr. Tim Meyer is a Senior Lecturer in Medical Oncology at the UCL Cancer Institute in London where he specialises in gastrointestinal cancers and drug development. He trained in medicine at UCL and obtained his PhD from London University, after which he completed specialist training in medical oncology. His major research focus is antibody-based vascular targeting.

	Vascular Disruptive Agentsfor the Treatment of Cancer	3
	Contents	5
	Contributors	7
	Development of Vascular Disrupting Agents	10
	1 Introduction	10
	2 Early Studies Supporting the Development of Vascular Disrupting Cancer Therapies	14
	2.1 Testicular Torsion	14
	2.2 William Henry Woglom	15
	2.3 Tumor Clamping Studies	15
	2.4 Coley’s Toxins	16
	3 Vascular Disrupting Therapies Employing High Molecular Weight Agents	17
	3.1 Engineered Ligands	17
	3.2 Antibody-Based Approaches	18
	3.3 Gene Therapy	19
	4 Small Molecule Vascular Disrupting Agents	21
	4.1 Metals and Metalloids	21
	4.2 Flavonoids/Xanthenones	21
	4.3 N-Cadherin Antagonists	22
	4.4 Colchicine	22
	4.5 Novel Vascular Disrupting Tubulin Depolymerizing Agents	23
	5 Combining VDAs with Other Therapies	25
	6 Clinical Experience with VDAs	26
	7 Concluding Remarks	28
	References	28
	Part I Pre-Clinical Development	37
	The Discovery and Characterisation of Tumour Endothelial Markers	38
	1 Vascular Tumor Targeting: Concepts and Definitions	38
	2 Methodologies for the Discovery of Vascular Tumor Targets	39
	3 Ligand-Based Pharmacodelivery Applications	42
	4 Validated Vascular Tumor Targets	43
	4.1 EDA and EDB Domains of Fibronectin	43
	4.2 Extra Domains of Within Tenascin-C	44
	4.3 Endoglin	44
	4.4 Prostate-Specific Membrane Antigen	45
	4.5 Annexin A1	45
	4.6 Phosphatidylserine Phospholipids	45
	4.7 VEGF-A and VEGF Receptors	46
	4.8 Integrins	46
	4.9 Robo4	46
	4.10 Other TEM’s Endosialin/TEM1 and TEM7	47
	5 Products in Clinical Development and Concluding Remarks	47
	References	49
	The Use of Animal Models in the Assessment of Tumour Vascular Disrupting Agents (VDAs)	56
	1 Introduction	56
	2 Animal Models	57
	2.1 General Considerations	57
	2.2 Subcutaneous and Other Ectopic Models	58
	2.3 Orthotopic and Metastatic Models	59
	2.4 Autochthonous Tumour Models	59
	2.5 Isolated Limb Perfusion in Rats	60
	2.6 Transgenic Knockout Mice	60
	2.7 Zebrafish	61
	3 Assays for Vascular Function	62
	3.1 General Considerations	62
	3.2 Blood Flow Rate	62
	3.3 High Frequency Micro-ultrasound	63
	3.4 Doppler Optical Coherence Tomography (DOCT)	65
	3.5 Laser Doppler Flowmetry and Near Infrared Spectroscopy	65
	3.6 Multifluorescence Microscopy	65
	3.7 Matrigel Plug Assay	67
	3.8 Intravital Video Microscopy	68
	4 Assays for Vascular Morphology	69
	4.1 Microvascular Corrosion Casting of Tumour Architecture	69
	4.2 Transmission Electron Microscopy (TEM)	69
	4.3 Confocal Laser Scanning Microscopy (CLSM) and Multi-Photon Fluorescence Microscopy (MPFM)	70
	5 Non-invasive Imaging	71
	5.1 General Considerations	71
	5.2 Bioluminescence/Fluorescence Imaging	71
	5.3 Nuclear Magnetic Resonance Spectroscopy (MRS) and Imaging (MRI)	72
	5.4 Positron Emission Tomography (PET)	75
	5.5 Scintigraphic Imaging of Tumour Hypoxia	75
	6 Other Assays	76
	6.1 Hollow Fibre Assay	76
	6.2 Wick-in-Needle Method for the Measurement of Interstitial Fluid Pressure (IFP)	76
	References	77
	Combination Therapy with Chemotherapy and VDAs	83
	1 Introduction	83
	2 Combining VDAs and Chemotherapy	84
	2.1 Complementary Targeting of Different Regions of the Tumor (Spatial Cooperation)	84
	2.2 Synergistic Activity on the Same Tumor Compartment	90
	2.3 Combination with Agents That Exploitthe Microenvironmental Changes Induced by VDAs	91
	2.4 Combination with Agents That Potentiate the Activityof VDAs, Reduce Resistance to Them or Limit Their Toxicity	91
	2.5 Modification in Blood Flow: Effects on Cytotoxic Drug Pharmacokinetics	92
	3 Sequencing and Timing	93
	4 Toxicity	95
	5 Conclusions	96
	References	97
	Lessons from Animal Imaging in Preclinical Models	100
	1 Magnetic Resonance Imaging of Tumour Vasculature	100
	2 Why Use MRI for VDA Assessment?	101
	3 Dynamic Contrast-Enhanced MRI	102
	3.1 Preclinical Assessment of ZD6126 Using DCE-MRI	103
	3.2 Preclinical Assessment of CA4P Using DCE-MRI	105
	3.3 Preclinical Assessment of DMXAA Using DCE-MRI	106
	3.4 Preclinical DCE-MRI Summary	107
	4 Susceptibility Contrast MRI	108
	4.1 Preclinical Assessment of VDAs Using Susceptibility Contrast MRI