Anti-vascular endothelial growth factor treatment in combination with chemotherapy delays hematopoietic recovery due to decreased proliferation of bone marrow hematopoietic progenitor cells

Introduction: Targeting of cancer by chemotherapy in combination with anti-vascular endothelial growth factor (VEGF) therapy has demonstrated not only the clinical efficacy but also a higher risk of serious hematologic complications including neutropenia. The purpose of the study was to elucidate the molecular mechanisms responsible for the development of neutropenia during the combination treatment. Methods: Mouse model and in vitro studies were undertaken to determine the effect of interference with VEGF signaling by VEGF-specific agents or a multitargeted VEGF receptor (VEGFR) tyrosine kinase inhibitor on proliferation of hematopoietic progenitor cell (HPC) and repopulation of the hematopoietic compartment after myeloablation. Results: The studies demonstrated that blockage of VEGFR1 or VEGFR2 signaling decreased HPC proliferation and impaired repopulation of the hematopoietic compartment after myelosuppression by slowing the progression of HPC through the cell cycle. The combination of cytotoxic drugs and VEGFR tyrosine kinase inhibitor had an additive inhibitory effect and decreased proliferation of HPC significantly stronger than either agent alone. Conclusions: Signaling through both VEGFR1 and VEGFR2 is required for normal reconstitution of the hematopoietic compartment after cytotoxic chemotherapy.