Practice question

Bevacizumab recombinant humanized IgG1 mAb 149 kDa neutralizes soluble VEGF-A isoforms 121 165 189 206 secreted tumor stromal inflammatory cells hypoxia HIF1alpha binding hypoxia response elements driving transcription. VEGF-A binds VEGFR1 FLT1 and R2 KDR tyrosine kinases endothelial cells dimerization autophosphorylation Tyr1175 recruiting PLC gamma generating IP3 DAG increasing calcium PKC stimulating proliferation permeability via VE-cadherin internalization gaps survival Akt phosphorylation caspase-9. Binding epitope Arg82 Lys84 affinity 0.5 nM overlapping receptor binding interface prevents ligand engagement suppresses downstream ERK activation inhibits new capillary sprouting pruning immature vessels lacking pericyte expressing Ang2 and normalizes remaining vasculature reducing interstitial fluid pressure 20 to 5 mmHg improving perfusion enhancing penetration co-administered cytotoxic drugs fluorouracil irinotecan. Approved metastatic colorectal first-line chemotherapy showing improvement PFS 10.6 vs 6.2 months non-small cell lung glioblastoma exemplifying anti-angiogenic strategy targeting microenvironment rather malignant cells directly requiring exclusion bleeding risk hemoptysis bowel perforation management hypertension side effect class effect.