Antiangiogenic and antitumor activity of 6-(2-aminoethyl)amino-5- chlorouracil, a novel small-molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap

Haiyan Lu, Robert S. Klein, Edward L. Schwartz

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TPare dependent on its enzyme activity. Experimental Design: A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo. Results: Oral administration of AEAC caused 40% to 50% reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions. Conclusion: These studies show antitumor activity for a drug targeting TPand suggest that inhibitors of TPcou ld be used to augment the clinical efficacy of drugs targeting the VEGF pathway.

Original languageEnglish (US)
Pages (from-to)5136-5144
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number16
DOIs
StatePublished - Aug 15 2009

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Thymidine Phosphorylase
Vascular Endothelial Growth Factor A
Neoplasms
Drug Delivery Systems
Microvessels
Heterografts
6-(2-aminoethyl)amino-5-chlorouracil
Vascular Endothelial Growth Factor Receptor
Angiogenesis Inducing Agents
Enzymes
Pancreatic Neoplasms
Human Activities
Non-Small Cell Lung Carcinoma
Oral Administration
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Antiangiogenic and antitumor activity of 6-(2-aminoethyl)amino-5- chlorouracil, a novel small-molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap",
abstract = "Purpose: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TPare dependent on its enzyme activity. Experimental Design: A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo. Results: Oral administration of AEAC caused 40{\%} to 50{\%} reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions. Conclusion: These studies show antitumor activity for a drug targeting TPand suggest that inhibitors of TPcou ld be used to augment the clinical efficacy of drugs targeting the VEGF pathway.",
author = "Haiyan Lu and Klein, {Robert S.} and Schwartz, {Edward L.}",
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T1 - Antiangiogenic and antitumor activity of 6-(2-aminoethyl)amino-5- chlorouracil, a novel small-molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap

AU - Lu, Haiyan

AU - Klein, Robert S.

AU - Schwartz, Edward L.

PY - 2009/8/15

Y1 - 2009/8/15

N2 - Purpose: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TPare dependent on its enzyme activity. Experimental Design: A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo. Results: Oral administration of AEAC caused 40% to 50% reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions. Conclusion: These studies show antitumor activity for a drug targeting TPand suggest that inhibitors of TPcou ld be used to augment the clinical efficacy of drugs targeting the VEGF pathway.

AB - Purpose: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TPare dependent on its enzyme activity. Experimental Design: A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo. Results: Oral administration of AEAC caused 40% to 50% reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions. Conclusion: These studies show antitumor activity for a drug targeting TPand suggest that inhibitors of TPcou ld be used to augment the clinical efficacy of drugs targeting the VEGF pathway.

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