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Vascular endothelial growth factor and vascular targeting of solid tumors
1The Hope Heart Institute, Department of Vascular Biology, Seattle, WA 98104-2046, USA. rbrekken@hopeheart.org
Abstract:
Vascular targeting agents, which selectively destroy tumor blood vessels, are attractive agents for the treatment of solid tumors. They differ from anti-angiogenic agents in that they target the mature, blood-conducting vessels of the tumors. They are better suited for larger tumors where angiogenesis can occur less frequently. For application in man, target molecules are needed that are selectively expressed on the vascular endothelium of tumors. Such markers include the complexes that are formed when vascular endothelial growth factor (VEGF) binds to its receptors (VEGFR). VEGF production by tumor cells is induced by oncogenic gene mutations and by the hypoxic conditions within the tumor mass. The receptors, VEGFR1 (FLT-1) and VEGFR2 (KDR/Flk-1), are upregulated on vascular endothelial cells in tumors by hypoxia and by the increased local concentration of VEGF. Consequently, there is a high concentration of occupied receptors on tumor vascular endothelium. Here, we review the concept of vascular targeting and the development of monoclonal antibodies that bind to VEGF: VEGFR complexes and their use as tumor vascular targeting agents. A promising monoclonal antibody is 2C3, which blocks VEGF from binding to VEGFR2 but not VEGFR1. We conclude that 2C3 might have dual activity as an anti-angiogenic agent by inhibiting VEGFR2 activity and as a vascular targeting agent for selective drug delivery to tumor vessels.
Insights
Vascular targeting agents offer a novel approach to treating solid tumors by selectively destroying tumor blood vessels. Monoclonal antibody 2C3 shows promise as a dual-action agent, inhibiting tumor growth and enabling targeted drug delivery.
Area of Science:
- Oncology
- Vascular Biology
- Immunotherapy
Background:
- Vascular targeting agents selectively destroy tumor vasculature, differing from anti-angiogenic agents by targeting mature vessels.
- These agents are particularly suited for larger tumors where angiogenesis is less prevalent.
- Target molecules on tumor vascular endothelium, such as vascular endothelial growth factor (VEGF) and its receptors (VEGFR), are crucial for therapeutic development.
Purpose of the Study:
- To review the concept of vascular targeting for cancer therapy.
- To discuss the development of monoclonal antibodies targeting VEGF:VEGFR complexes.
- To evaluate the potential of antibody 2C3 as a tumor vascular targeting agent.
Main Methods:
- Review of existing literature on vascular targeting agents and monoclonal antibodies.
- Focus on antibodies that bind to VEGF:VEGFR complexes on tumor vasculature.
- Analysis of antibody 2C3's binding specificity and potential mechanisms of action.
Main Results:
- VEGF production is induced by oncogenic mutations and hypoxia, leading to upregulated VEGFRs on tumor vascular endothelium.
- High concentrations of occupied receptors are found on tumor vascular endothelium.
- Monoclonal antibody 2C3 specifically blocks VEGF binding to VEGFR2, not VEGFR1.
Conclusions:
- Antibody 2C3 demonstrates potential as a dual-action therapeutic agent.
- It may function as an anti-angiogenic agent by inhibiting VEGFR2 activity.
- 2C3 could also serve as a vascular targeting agent for selective drug delivery to tumor vessels.