Decrease in tumor cell oxygen consumption after treatment with vandetanib (ZACTIMA; ZD6474) and its effect on...

Area of Science:

• Oncology
• Pharmacology
• Radiotherapy

Background:

• Vascular Endothelial Growth Factor (VEGF) signaling promotes tumor angiogenesis and hypoxia.
• VEGF inhibitors are investigated for cancer therapy, but their effects on tumor oxygenation and combination treatments require clarification.

Purpose of the Study:

• To investigate the early effects of vandetanib, a VEGFR inhibitor, on tumor oxygenation and its impact on combining vandetanib with radiotherapy.
• To assess how vandetanib influences tumor oxygen consumption, perfusion, and radiation sensitivity.

Main Methods:

• Utilized transplantable liver tumors in mice, administering daily doses of vandetanib (25 mg/kg).
• Measured tumor oxygenation (pO(2)) and cellular oxygen consumption via electron paramagnetic resonance (EPR).
• Assessed tumor perfusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and evaluated radiation sensitivity through regrowth delay assays.

Main Results:

• Vandetanib treatment led to an early increase in tumor oxygenation, independent of vascular remodeling or perfusion changes.
• A significant decrease in tumor cell oxygen consumption was observed, likely causing the increased oxygenation.
• Vandetanib potentiated the tumor response to radiotherapy, consistent with improved oxygenation.

Conclusions:

• Inhibitors of VEGFR signaling, such as vandetanib, reduce tumor cell oxygen consumption rates.
• The observed early increase in tumor oxygenation by vandetanib has significant implications for optimizing the timing and sequencing of combination therapies involving VEGF inhibitors and radiation.