TY - JOUR
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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U2 - 10.1158/1078-0432.CCR-08-3203
DO - 10.1158/1078-0432.CCR-08-3203
M3 - Article
C2 - 19671868
AN - SCOPUS:69349099903
SN - 1078-0432
VL - 15
SP - 5136
EP - 5144
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -