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32 Cards in this Set

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  • Back
What is angiogenesis?
Formation of new vessels from existing endothelial cells and endothelial progenitor cells present in the bone marrow
What is Arteriogenesis?
Remodeling of pre-existing channels by mesenchymal cells
What is vasculogenesis?
Initial formation of blood vessels in the embryo by vascular precursor cells
What have been the results in VEGF/FGF therapy for Human Clinical Trials?
Increased vesel density, salvage of limbs, and decreased ulceration in ischemic limb disease
Decreased Angina and Ischemia after MI
What has there not been a clinical benefit for with VEGF/FGF therapy?
No clinical benefit in treatment of Coronary Artery Disease
What is the current protocol for VEGF/FGF therapy and would a better protocol be?
Current: Single drug (VEGF), Short Term, Older Pts.
Better: More than one drug, Long term; b/c angiogenesis requires more then one molecule in a sequence, like Angiopoitin, TGF-B, etc.
What could an Alternate method be for Angiogenesis stimulation?
Targe HIFs and get an increase in ALL molecules
What are the side effects of Angiogenic Stimulation by VEGF/EGF?
Both VEGF/EGF cause NO mediated hypotension
VEGF causes edema from vessel immaturity and increased permeability
Acceleration of Tumor Growth in preexisting malignacy
What is Anti-Angiogenic therapy used for besides Chronic Inflammation?
Treatment of Tumor Growth and Metatisis
Tumor's do NOT grow beyond 1 mm unless they obtain additional blood vessels
How is Angiogenesis involved in Chronic Inflammation: Rheumatoid Arthritis, Chrohn's, Psoriasis?
Inflammation attracts Leukocytes which stimulates the relasea of VEGF & MMP's
Increase vascularity and High VEGF correlate with degree of tissue destruction
High levels of what are indicatorsfor higher degree of tissue damage?
What are the 3 ways to inhibit Angiogenesis?
Anti-Integrin (AB: Medi-522) to integrin; decrese leukocyte adhesion to endothelial cells which is crucial for migration
Anti-TNF (AB: Infliximab) decreases VEGF production and Leukocyte adhesion
Thalidomide: Inhibits TNF
What do Tumors that are <1 mm do in the body?
Asymptomatic Microscopic Tumors: DO NOT CAUSE DISEASE
DO NOT stimulate angiogenesis
Presence of dormant tumors is quite common and often go undiagnosed
To grow require Angiogenic Switch
How is angiogenic switch determined?
Ratio of angiogenic inhibitors to angiogenic activatos determines angiogenic switch
When is cell division rare and when is it frequent in an angiogenic switch?
Rare: High inhibitor levels; Low activator levels = Dormant Tumor
Frequent: Low ihibitor levels; High activator levels = Growing Tumors
What causes an Angiogenic Switch in Tumor Cells?
Tumor Cell Accumulation of HIF's; which induces synthesis of VEGF, FGF and MMPs
Levels of what correlate with progression of disease and clinical outcome?
Levels of VEGF corrlate with progression of disease and clinical outcome
Increased levels indicate greater disease progression
What causes increased levels of HIF?
Loss of function of p53
Proto-oncogenes converted to Oncogene (hyperactive)
What is p53 and what does it do?
It is a tummor suppressor by suppressing HIFs
Loss of function in cancer leads to increased HIFs
How does Proto-oncogenes convert to oncogenes or "gain their function"?
The mutation is associated with an increase in HIFs
Ex: SRC kinase?
What are the consequences to Tumor Angiogenesis?
Tumore Grows
Abnormal blood flow may impair delivery of chemo drugs
Increased permeability and size in Lymp may facilitate metastases
Decreased adhesion receptors decreases the Immune Response
What may happen after the removal of a Primary tumor and what has shown to improve the outcome in mice?
Removal of the primary tumor may result in metastic growth
Mice (w/removed tumor) given urine from a mouse that still had a primary tumor there was no metastisis
What would you treat Early Tumor growth with?
Anti-VEGF which targets Endothelial cells
What would you treat a later progression of a tumor with?
Anti-PDGF, Angiopoiten and TGF-B which targets Mesenchymal cells
What drug would target multiple stimulators and what does it do?
NEOVASTAT: A natural compound from cartiledge (avascular)
Blocks VEGF, Inhibits MMP, Promotes Apop. of Endo cells,
What is a drug that targets multiple cell types of tumor growth and what does it do?
Cox-2 Inhibitor (Celecoxib, Rofecoxib)
Targets Endothelium, tumor cells, Inflamm. Cells, Inhibits VEGF release from Tumor and promotes T cell
What are the advantages of Anti-Angiogenic Therapy?
Solid-Tumors are angiogenis dependent
Chronic Inflammation is less exacerbated
No known toxicity with endo inhibitors
Few side effecs
Similar targets across variety of tumors
Endo cells do not mutate
Easier to target vessels
What are some disadvantages of Anti-Angiogenic Therapy?
May require chronic administration
Manufacturing limitations
Long term side effects unknown
Development of resistance
What arm of cancer treatment is Anti-Angiogenetic therapy?
The fourth arm
1. Surgery
2. Radiation
3. Chemotherapy
What can Anti-Angiogenic Therapy be combined with?
Metronomic Chemotherapy
Which targets tumor proliferation and the growth of new vessels
What is the therapeutic goal of cancer treatment?
Eradication is NOT likely
Tumor Arrest and Prevention of growth of Microscopic tumors
How do you monitor potenital Angiogenic Switching?
First measure # of circulating endothelial progenitors
Determine the # of stimulators vs. inhibitors
Measure MMPs in urine