Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668

Darren W. Davis, Ryan Takamori, Chandrajit P. Raut, Henry Q. Xiong, Roy S. Herbst, Walter M. Stadler, John V. Heymach, George D. Demetri, Asif Rashid, Yu Shen, Sijin Wen, James L. Abbruzzese, David McConkey

Research output: Contribution to journalArticle

Abstract

Purpose: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. Experimental Design: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. Results: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly (≈50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. Conclusions: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Original languageEnglish (US)
Pages (from-to)678-689
Number of pages12
JournalClinical Cancer Research
Volume11
Issue number2 I
StatePublished - Jan 15 2005
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor
Cell Death
Endothelial Cells
Neoplasms
Platelet-Derived Growth Factor Receptors
Heterografts
Apoptosis
Vascular Endothelial Growth Factor Receptor-2
Microvessels
orantinib
Semaxinib
Laser Scanning Cytometry
Phosphorylation
Biopsy
Maximum Tolerated Dose
Growth
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668. / Davis, Darren W.; Takamori, Ryan; Raut, Chandrajit P.; Xiong, Henry Q.; Herbst, Roy S.; Stadler, Walter M.; Heymach, John V.; Demetri, George D.; Rashid, Asif; Shen, Yu; Wen, Sijin; Abbruzzese, James L.; McConkey, David.

In: Clinical Cancer Research, Vol. 11, No. 2 I, 15.01.2005, p. 678-689.

Research output: Contribution to journalArticle

Davis, DW, Takamori, R, Raut, CP, Xiong, HQ, Herbst, RS, Stadler, WM, Heymach, JV, Demetri, GD, Rashid, A, Shen, Y, Wen, S, Abbruzzese, JL & McConkey, D 2005, 'Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668', Clinical Cancer Research, vol. 11, no. 2 I, pp. 678-689.
Davis, Darren W. ; Takamori, Ryan ; Raut, Chandrajit P. ; Xiong, Henry Q. ; Herbst, Roy S. ; Stadler, Walter M. ; Heymach, John V. ; Demetri, George D. ; Rashid, Asif ; Shen, Yu ; Wen, Sijin ; Abbruzzese, James L. ; McConkey, David. / Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 2 I. pp. 678-689.
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abstract = "Purpose: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. Experimental Design: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. Results: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50{\%} and 92{\%}, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly (≈50{\%}) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. Conclusions: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.",
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AU - Davis, Darren W.

AU - Takamori, Ryan

AU - Raut, Chandrajit P.

AU - Xiong, Henry Q.

AU - Herbst, Roy S.

AU - Stadler, Walter M.

AU - Heymach, John V.

AU - Demetri, George D.

AU - Rashid, Asif

AU - Shen, Yu

AU - Wen, Sijin

AU - Abbruzzese, James L.

AU - McConkey, David

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N2 - Purpose: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. Experimental Design: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. Results: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly (≈50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. Conclusions: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

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