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Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition

Abstract

Contrary to initial expectations, angiogenesis inhibitors can cause toxicities in patients with cancer. The toxicity profiles of these inhibitors reflect the disturbance of growth factor signalling pathways that are important for maintaining homeostasis. Experiences with angiogenesis inhibitors in clinical trials indicate that short-term toxicities are mostly manageable. However, these agents will also be given in prolonged treatment strategies, so we need to anticipate possible long-term toxicities. In addition, understanding the molecular mechanisms involved in the toxicity of angiogenesis inhibition should allow more specific and more potent inhibitors to be developed.

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Figure 1: The various biological functions of VEGF.
Figure 2: Platelet–endothelial cell interactions and the anti-coagulatory activity of the quiescent endothelium.
Figure 3: Angiogenic growth factor stimulation of the endothelium causes concomitant activation of the coagulation cascade and angiogenesis.
Figure 4: Blood pressure regulation by the vascular system.

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Acknowledgements

H.V. is a recipient of the American Society of Clinical Oncology (ASCO) Young Investigator's award 2006 and of a Drug Development fellowship at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institution. This work was supported in part by The Adriana van Coevorden Society (H.V.) and for a major part by the Spinoza award (H.M.P.).

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Glossary

Acral erythema

Redness of the most distal extremities caused by capillary congestion (a general sign of inflammation).

Baroreceptors

Located in the carotid arteries in the neck, these receptors are stretched by high blood pressure, reducing the activation of the vasomotor centre. They also activate the vasomotor centre in response to low blood pressure.

Dendritic cells

Immune cells that process antigens and present them to other immune cells.

Encephalopathy

Alteration in brain function and/or structure. Common symptoms include progressive loss of memory and cognitive ability, subtle personality changes, inability to concentrate, lethargy and progressive loss of consciousness.

Gastrointestinal perforations

Can occur in the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity.

Glomerulus

A capillary bed surrounded by the Bowman's capsule in the kidney, which regulates blood filtration and urine generation.

Ischaemia

An inadequate blood supply to an organ.

Left ventricular ejection fraction

The fraction of blood pumped out of the left ventricle with each heart beat.

Leukopenia and lymphopenia

A low leukocyte or lymphocyte count in the circulating blood, both of which increase the risk of infections.

Megakaryocytes

The precursor cells of platelets, located in the bone marrow.

Perivascular cells

Cells that surround vessels, including pericytes, myofibroblasts and smooth muscle cells.

Podocytes

Cells that form the visceral epithelium in the kidney and are involved in the glomerular filtration barrier.

Reversible posterior leukoencephalopathy syndrome

A rapidly evolving neurological syndrome. The underlying mechanism seems to be related to an increased permeability and reactivity of brain vasculature.

Subungual splinter bleeding

A small amount of bleeding that occurs under a finger or toe nail.

Thrombocytopenia

A low platelet count in the circulating blood.

Vascular resistance

The resistance to flow that must be overcome to push blood though a vessel; determined by diameter, stiffness and length of the vessel.

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Verheul, H., Pinedo, H. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7, 475–485 (2007). https://doi.org/10.1038/nrc2152

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