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The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor
D B Mendel1, R E Schreck, D C West
1SUGEN, Inc., South San Francisco, California 94080, USA. Dirk-Mendel@sugen.com
Abstract:
SU5416, a selective inhibitor of the tyrosine kinase activity of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR, is currently in Phase III clinical trials for the treatment of advanced malignancies. In cellular assays, SU5416 inhibits the VEGF-dependent mitogenic/proliferative response of human umbilical vein endothelial cells (HUVECs). In tumor xenograft models, SU5416 inhibits the growth of tumors from a variety of origins by inhibiting tumor angiogenesis. In three different human tumor xenograft models, infrequent (once or twice a week) administration of SU5416 is efficacious despite the fact that it has a short plasma half-life (30 min), which suggests that SU5416 has long-lasting inhibitory activity in vivo. The goal of the present study was to determine the basis for the prolonged activity of SU5416. The results indicate that a short (3 h) exposure to 5 microM SU5416 (to mimic plasma levels of the compound as measured in patients who were receiving SU5416 therapy) produced long-lasting (at least 72 h) inhibition of the VEGF-dependent proliferation of HUVECs in culture, which indicate that SU5416 has long-lasting inhibitory activity in vitro as well as in vivo. SU5416 treatment of HUVECs did not affect surface expression of Flk-1/KDR or the affinity of the receptor for VEGF. Instead, the durability of the in vitro activity of SU5416 was shown to be attributable to its long-lasting ability to specifically inhibit VEGF-dependent phosphorylation of Flk-1/KDR and subsequent downstream signaling, although SU5416 is not an irreversible inhibitor of Flk-1/KDR tyrosine kinase activity. The long-lasting inhibition of cellular responses to VEGF was attributable to the accumulation of SU5416 in cells, as shown using radiolabeled compound, such that inhibitory cellular concentrations of SU5416 are maintained long after the removal of the compound from the medium. The long-lasting inhibitory activity of SU5416 in vitro is consistent with the finding that SU5416 has demonstrated evidence of biological activity in clinical studies when administered twice a week despite a short plasma half-life.
Insights
SU5416, a vascular endothelial growth factor receptor inhibitor, shows prolonged anti-cancer activity despite a short half-life. This is due to its accumulation within cells, maintaining inhibition of tumor growth and angiogenesis.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- SU5416 is a vascular endothelial growth factor (VEGF) receptor kinase inhibitor in clinical trials for advanced cancers.
- SU5416 inhibits tumor growth by blocking tumor angiogenesis.
- Clinical efficacy of SU5416 suggests prolonged activity despite a short plasma half-life.
Purpose of the Study:
- To investigate the basis for the prolonged in vitro and in vivo activity of SU5416.
- To understand the mechanism behind SU5416's sustained efficacy in cancer treatment.
Main Methods:
- Assessed SU5416's effect on VEGF-dependent proliferation of human umbilical vein endothelial cells (HUVECs).
- Investigated the impact of SU5416 on Flk-1/KDR receptor expression and VEGF binding affinity.
- Utilized radiolabeled SU5416 to determine compound accumulation within cells.
Main Results:
- Short exposure to SU5416 resulted in long-lasting inhibition of VEGF-dependent HUVEC proliferation.
- SU5416 did not alter Flk-1/KDR surface expression or VEGF affinity.
- Prolonged inhibition was attributed to SU5416 accumulation in cells, maintaining effective concentrations.
Conclusions:
- SU5416 exhibits durable inhibitory activity against VEGF signaling pathways.
- Intracellular accumulation of SU5416 underlies its sustained anti-cancer effects.
- Findings support the clinical observation of SU5416 efficacy with infrequent dosing schedules.