Prevention of Hypoxia-Induced Apoptosis by the Angiogenic Factor Thymidine Phosphorylase

doi:10.1006/bbrc.1998.9852

Biochemical and Biophysical Research Communications

Volume 253, Issue 3, 30 December 1998, Pages 797-803

https://doi.org/10.1006/bbrc.1998.9852 Get rights and content

Abstract

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is expressed at higher levels in a wide variety of solid tumors compared to adjacent normal tissues. Patients with PD-ECGF/TP-positive colon and esophageal tumors have a poorer prognosis than those with negative tumors. The expression of PD-ECGF/TP is a prognostic factor independent of microvessel density suggesting that TP has effects on tumor progression independent of its angiogenic activity. Evidence that hypoxia and apoptosis affect tumor growth prompted us to determine whether increased expression of PD-ECGF/TP prevents apoptosis induced by hypoxia. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF/TP, 2-deoxy-D-ribose and thymine partially prevented hypoxia-induced apoptosis. The ability of 1 μM 2-deoxy-D-ribose in combination with the same concentration of thymine to prevent hypoxia-induced apoptosis was similar to that of the overexpressed TP in KB cells. A concentration of 1 μM 2-deoxy-L-ribose abrogated the effects of these degradation products of thymidine. These findings suggested that TP can confer resistance to apoptosis induced by hypoxia and the degradation products of thymidine are involved in this resistance. Expression of PD-ECGF/TP may play an important role in the progression of solid tumors, and inhibitors of TP and analogs of the degradation products of thymidine may suppress the growth of tumors by promoting apoptosis.

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Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, maintaining nucleoside homeostasis for DNA repair and replication. In many cancers TP is expressed at high levels and promotes thymidine catabolism, ultimately generating 2-deoxyribose (2dDR) that can support multiple procancer processes, including glycation of proteins, alternative metabolism, extracellular matrix remodeling, and angiogenesis. Therefore, inhibition of TP is an attractive anticancer strategy; however, an alternative approach that exploits the catalytic activity of TP to activate 5-fluorouracil (5-FU) prodrugs has been clinically successful. Here, we review the structure, function, and regulation of TP, its multiple supporting roles in cancer growth and survival. We summarize TP inhibitor and prodrug development and propose TP-targeting strategies that could potentiate the action of current therapies.
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Citation Excerpt :
In particular, focusing on the signaling pathways mediated by TYMP in endothelial cells may clarify its angiogenic effect and lead to the development of additional pro- or anti-angiogenic therapeutics. In 1998, Kitanozo et al. [11] found that expression of TYMP in colon and esophageal tumors was a prognostic factor independent of microvessel density. This finding led them to speculate that TYMP may affect tumor progression independently of its angiogenic effect.
We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.
Recent discovery of non-nucleobase thymidine phosphorylase inhibitors targeting cancer
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Thymidine phosphorylase (TP, EC 2.4.2.4), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexpression of many angiogenic factors such as matrix metalloproteases (MMPs), interleukins (ILs), vascular endothelial growth factor (VEGF) etc., resulting in promotion of angiogenesis and cancer metastasis. In addition, overshooting TP level protects tumour cells from apoptosis and helps cell survival. Thus, TP is identified as a prime target for developing novel anticancer therapies. Pioneering research activities investigated a large number of TP inhibitors, most of which are pyrimidine or purine analogues. Recently, an array of structurally diverse non-nucleobase derivatives was designed, synthesized and established as promising TP inhibitors. This review, following an outline on the TP structure and functions, gives an overview of the recent advancement of various non-nucleobase TP inhibitors as novel anti-cancer agents.
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^☆: Abbreviations: TP, thymidine phosphorylase; PD-ECGF, platelet-derived endothelial cell growth factor; VEGF, vascular endothelial growth factor

¹: These authors contributed equally to this work.

²: To whom correspondence should be addressed at Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan. Fax: 81-992-65-9687.

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Regular ArticlePrevention of Hypoxia-Induced Apoptosis by the Angiogenic Factor Thymidine Phosphorylase☆

Abstract

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Regular Article
Prevention of Hypoxia-Induced Apoptosis by the Angiogenic Factor Thymidine Phosphorylase☆