Our studies have focused on the angiogenic factor PD-ECGF (platelet-derived endothelial cell growth factor), one of several polypeptide factors that are produced by tumor epithelial and stromal cells and that promote tumor angiogenic activity. Sequencing of the of human PD-ECGF cDNA revealed it to be identical to human thymidine phosphorylase (TP), an enzyme which catalyzes the conversion of thymidine to thymine and 2-deoxyribose-1-phosphate (dR-1-P). Tumor xenografts grew more rapidly and were more highly vascularized when derived from cells that were transfected with TP, and there are extensive clinical data correlating elevated TP expression in human solid tumors with increased microvessel density, increased tumor invasiveness, and poor patient prognosis. Unlike VEGF and other cytokines, TP is not directly angiogenic, rather its effects are due to its catalytic activity. In the previous grant period, we defined the mechanisms regulating TP transcription in tumors and in monocytes, obtained definitive evidence that the angiogenic actions of TP are mediated by 2-deoxyribose (2dR) which is formed intracellularty from dR-1-P and then released from cells expressing TP, showed that 2dR is a chemotactic factor for human endothelial cells (HUVEC), provided the first data illustrating an effect of 2dR on integrin-related signaling pathways in HUVEC, and identified and synthesized an inhibitor of TP activity and of TP-induced HUVEC migration. We propose to extend these studies in the next grant period, specifically to: 1) determine if 2dR's actions are mediated by its activation of the VEGF receptor-2 and/or VEGF receptor-3; 2) test the hypothesis that microvascular endothelial cells (EC), and lymphatic EC in particular, will be highly responsive to 2dR; 3) determine if 2dR acts on inside/out and/or outside/in integrin signaling pathways; 4) determine if 2dR protects EC from apoptosis; 5) determine if there is a specific 2dR receptor in EC, and 6) use a human lung cancer heterotransplant mouse model in which tumors contain human EC to evaluate the in vivo anti- angiogenic and anti-tumor activities of agents targeting TP, alone and in combination with a VEGF inhibitor. The long term objectives of this project are to define the molecular mechanisms regulating the anti- angiogenic actions of TP, and to determine whether targeting TP-mediated angiogenic pathways is a viable therapeutic approach to treat cancer. This information could lead to new drug treatments for cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA089352-05A1
Application #
7105800
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2000-12-01
Project End
2011-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$230,213
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
041581026
City
New York
State
NY
Country
United States
Zip Code
10467
Dalyot-Herman, Nava; Delgado-Lopez, Fernando; Gewirtz, David A et al. (2009) Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules. Biochem Pharmacol 78:1167-77
Schwartz, Edward L (2009) Antivascular actions of microtubule-binding drugs. Clin Cancer Res 15:2594-601
Lu, Haiyan; Klein, Robert S; Schwartz, Edward L (2009) 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. Clin Cancer Res 15:5136-44
Hotchkiss, Kylie A; Ashton, Anthony W; Schwartz, Edward L (2003) Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3. J Biol Chem 278:19272-9
Zhu, Geng Hui; Schwartz, Edward L (2003) Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin. Mol Pharmacol 64:1251-8
Zhu, Geng Hui; Lenzi, Michelle; Schwartz, Edward L (2002) The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. Oncogene 21:8477-85
Hotchkiss, Kylie A; Ashton, Anthony W; Mahmood, Radma et al. (2002) Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther 1:1191-200