When is angiogenesis promotion or inhibition used in treatment, and what therapies are involved?

Angiogenesis in Medical Treatment: Promotion and Inhibition Strategies

Angiogenesis modulation is primarily used in two opposing therapeutic contexts: promotion of angiogenesis for ischemic conditions like peripheral arterial disease and inhibition of angiogenesis for cancer and certain ocular diseases. 1, 2

Angiogenesis Inhibition Therapies

Cancer Treatment

Angiogenesis inhibition represents a cornerstone of modern cancer therapy, targeting the tumor's ability to develop its own blood supply:

• FDA-approved anti-angiogenic agents:

  • Bevacizumab (Avastin): A humanized monoclonal antibody that neutralizes vascular endothelial growth factor (VEGF), approved for:
    • Metastatic colorectal cancer (first or second-line treatment)
    • Non-squamous non-small cell lung cancer
    • Recurrent glioblastoma
    • Metastatic renal cell carcinoma
    • Persistent/recurrent cervical cancer
    • Epithelial ovarian, fallopian tube, or primary peritoneal cancer 2

• Mechanism of action: These therapies work by blocking the formation of new blood vessels that supply tumors with oxygen and nutrients, thereby limiting tumor growth and metastasis 3

• Clinical considerations:

  • Significant adverse effects include:
    • Gastrointestinal perforations
    • Wound healing complications
    • Hemorrhage
    • Arterial and venous thromboembolic events
    • Hypertension
    • Proteinuria and renal injury
    • Congestive heart failure 2

Ocular Diseases

Anti-angiogenic therapy is also used for:

• Diabetic retinopathy
• Age-related macular degeneration
• Other conditions with pathological ocular neovascularization 3

Angiogenesis Promotion Therapies

Peripheral Arterial Disease (PAD)

• Target population: Affects 6% of individuals aged 50-60 years and 10-20% of those over 70 years 1
• Clinical need: Current therapies for improving lower limb perfusion in PAD are largely ineffective 1

Therapeutic Angiogenesis Approaches

1. Growth Factor Therapy:

   • Key factors: Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2)
   • Delivery methods:
     • Protein delivery
     • Gene therapy using adenovirus-mediated transfer 1, 4
   • Clinical status: Despite promising results in animal models, clinical trials have shown limited efficacy in humans 1, 4
   • Challenges: The failure may be related to deficiency in nitric oxide release in patients with endothelial dysfunction 1
   • Potential solutions: Adjuvant therapy with L-arginine or inhibitors of oxidative stress may increase effectiveness 1

2. Combination Growth Factor Therapy:

   • Rationale: Single growth factors may not be sufficient for sustainable angiogenesis
   • Example: Combined use of VEGF and angiopoietin-1 (Ang-1) may lead to more mature vascular networks 5
   • Mechanism: Complementary actions of different factors targeting multiple angiogenic pathways 5, 6

3. Cell-Based Therapies:

   • Cellular cardiomyoplasty: Implanting precursor muscle cells into areas of myocardial infarction
   • Cell types: Human embryonic stem cells, fetal cardiac muscle cells, skeletal muscle myoblasts, peripheral and bone marrow stem cells 1, 7
   • Clinical status: Phase I trials have demonstrated feasibility and safety, but optimization is still needed 1

Coronary Artery Disease Applications

• Target population: 10-12% of patients with severe coronary artery disease who are not candidates for standard revascularization 1
• Approach: Therapeutic angiogenesis to induce cardiac neorevascularization
• Delivery methods: Direct intramyocardial injection, intracoronary infusion, or retrograde coronary sinus infusion 1

Challenges and Future Directions

1. Translational Barriers:

   • Gap between animal model success and clinical efficacy
   • Need for better understanding of endothelial dysfunction in patients 1

2. Monitoring and Assessment:

   • Need for advanced imaging technologies to assess angiogenic therapy efficacy
   • CT, MRI, and PET allow for real-time perfusion, anatomical and functional imaging 1

3. Safety Concerns:

   • Potential for pro-angiogenic therapies to induce alterations in neural networks of the heart
   • Risk of arrhythmias and other cardiovascular complications 1
   • For anti-angiogenic therapies, significant risks of bleeding, thrombosis, and impaired wound healing 2

4. Delivery Optimization:

   • Development of minimally invasive techniques for growth factor or gene administration
   • Determining appropriate cell dose and procedures to prevent cell loss in cell-based therapies 1

5. Novel Approaches:

   • Targeting vessel co-option (tumor cells using existing vasculature) in addition to angiogenesis 1
   • Development of combined therapies targeting multiple angiogenic pathways 5, 6

The field of angiogenesis modulation continues to evolve with promising therapeutic potential, though significant challenges remain in translating preclinical success to clinical efficacy, particularly for pro-angiogenic therapies.