Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity

Usuki, Kensuke; Saras, Jan; Waltenberger, Johannes; Miyazono, Kohei; Pierce, Glenn F.; Thomason, Arlen; Heldin, Carl‐Henrik

doi:10.1016/s0006-291x(05)80025-7

Cited by 184 publications

(89 citation statements)

References 14 publications

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“…PD-ECGF is an endothelial cell mitogen of relative molecular mass purified to homogeneity from human platelets, and has chemotactic activity for endothelial cells in vitro and angiogenic activity in vivo (Ishikawa et al, 1989). In 1992, PD-ECGF was identified as being homologous to thymidine phosphorylase (dThdPase), which catalyses the reversible phosphorylation of thymidine to thymine and 2-deoxyribose-1-phosphate (Furukawa et al, 1992;Usuki et al, 1992); this enzymatic activity is crucial for the angiogenic activity. Takahashi et al (1996) have demonstrated that PD-ECGF was expressed in infiltrating cells in most of colon cancers, but rarely in tumour epithelium.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of angiogenesis in human pancreatic cancer

et al. 1999

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To evaluate whether angiogenic factors are of clinical relevance to actual human pancreatic cancers, we studied the intratumoral microvessel density (IMD), and PD-ECGF, VEGF protein expression in 40 pancreatic cancers using immunohistochemistry. We also investigated PD-ECGF and VEGF gene expression using reverse transcriptase-PCR (RT-PCR). Of the 40 pancreatic cancers studied, 30 carcinomas (75.0%) were evaluated to be PD-ECGF -positive and 10 carcinomas (25.0%) were determined to be PD-ECGF -negative. In contrast, 27 carcinomas (67.5%) were evaluated to be VEGF -positive, whereas 13 carcinomas (32.5%) were VEGF -negative. VEGF gene expression was moderately associated with an increase in the IMD ( r 2 = 0.181, P = 0.006), but no significant relationship was found between PD-ECGF gene expression and the IMD ( r 2 = 0.093, P = 0.059). However, tumours with positive expression for both PD-ECGF and VEGF had a higher IMD ( P = 0.027). The results of the immunohistochemistry agreed well with the results of the quantitative RT-PCR. The median survival time of the hypervascular group was significantly shorter than that of the hypovascular group ( P < 0.0001). In comparing the survival according to PD-ECGF and VEGF gene expression, the median survival time of the patients with positive PD-ECGF expression was significantly shorter than those with negative PD-ECGF expression ( P = 0.040). Furthermore, the median survival time of the patients with positive VEGF expression was significantly shorter than those with negative VEGF expression ( P = 0.048). However, the Cox multivariate analysis indicated that the IMD and VEGF expression were independent prognostic factors of the various clinicopathologic variables in pancreatic cancer patients ( P = 0.0021 and P = 0.0443, respectively). © 1999 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of angiogenesis in human pancreatic cancer

et al. 1999

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“…1,3,4 TP, an enzyme catalyst in the reversible phosphorylation of thymidine to thymine and deoxyribe-1-phosphate, is identical to PD-ECGF 7 and has several biologic actions, including chemotactic activity of endothelial cells and angiogenic activity in vivo. [5][6][7][8] In addition, the metabolite, deoxyriose-1-phosphate, showed angiogenic activity. Very recently, Mori et al 33 reported that the angiogenesis inhibitor TNP-470 suppressed tumor angiogenesis and tumor growth of lung squamous cell lines in parallel with the suppression of TP but not of VEGF or bFGF.…”

Section: Discussionmentioning

confidence: 99%

Thymidine phosphorylase and vascular endothelial growth factor in patients with Stage I lung adenocarcinoma

Kojima

Shijubo

Abe

2002

Cancer

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Sleeping giants: As a mimic of cell agglomeration to form tissues, a novel vesicle aggregation process with the characteristic advantages of being highly efficient, light‐responsive, reversible, large‐scale, and stable is reported. Giant hyperbranched polymer vesicles (5–10 μm) are used as the building blocks (see scheme), and the vesicle aggregates can assemble and disassemble with alternating UV and Vis irradiation.

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“…The angiogenic protein, platelet-derived endothelial cell growth factor, isolated from platelets in 1987, was shown to be identical to TPase (3). Mutational analysis revealed that the enzymatic activity of TPase is essential for its angiogenic effect (4).…”

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The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Liekens

Hernández

Ribatti

et al. 2004

Journal of Biological Chemistry

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Thymidine phosphorylase (TPase) catalyzes the reversible phosphorolysis of pyrimidine deoxynucleosides to 2-deoxy-D-ribose-1-phosphate and their respective pyrimidine bases. The enzymatic activity of TPase was found to be essential for its angiogenesis-stimulating properties. All of the previously described TPase inhibitors are either pyrimidine analogues that interact with the nucleosidebinding site of the enzyme or modified purine derivatives that mimic the pyrimidine structure and either compete with thymidine or act as a multisubstrate (competitive) inhibitor. We now describe the inhibitory activity of the purine riboside derivative KIN59 (5 -O-tritylinosine) against human and bacterial recombinant TPase and TPase-induced angiogenesis. In contrast to previously described TPase inhibitors, KIN59 does not compete with the pyrimidine nucleoside or the phosphate-binding site of the enzyme but noncompetitively inhibits TPase when thymidine or phosphate is used as the variable substrate. In addition, KIN59 was far more active than other TPase inhibitors, previously tested by us, against TPase-induced angiogenesis in the chorioallantoic membrane assay. The observed anti-angiogenic effect of KIN59 was not accompanied by inflammation or any visible toxicity. Inosine did not inhibit the enzymatic or angiogenic activity of the enzyme, indicating that the 5 -O-trityl group in KIN59 is essential for the observed effects. In contrast with current concepts, our data indicate that the angiogenic activity of TPase is not solely directed through its functional nucleoside and phosphate-binding sites. Other regulatory (allosteric) site(s) in TPase may play an important role in the mechanism of TPase-triggered angiogenesis stimulation and apoptosis inhibition. Identification of these site(s) is important to obtain a better insight into the molecular role of TPase in the progression of cancer and angiogenic diseases.Angiogenesis is the process by which new blood vessels arise from pre-existing vessels (1). It is essential during embryogenesis for the formation of a vascular plexus, which ensures an adequate blood supply to all developing tissues. In adults, neovascularization is limited to wound healing and the female reproductive cycle. During these processes, angiogenesis is tightly regulated. Unregulated angiogenesis may lead to the progression of several inflammatory diseases and is an essential component of solid tumor growth and metastasis. The formation of new blood vessels requires several sequential steps, which are regulated by a number of angiogenic factors, including chemokines, growth factors, integrins, and enzymes, such as proteases and thymidine phosphorylase (TPase) 1 (1).TPase is an enzyme that catalyzes the reversible phosphorolysis of pyrimidine 2Ј-deoxynucleosides to 2-deoxyribose 1-phosphate and their respective pyrimidine bases. TPase also recognizes several nucleoside analogues that are being used clinically as antiviral

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Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity

Cited by 184 publications

References 14 publications

Prognostic significance of angiogenesis in human pancreatic cancer

Prognostic significance of angiogenesis in human pancreatic cancer

Thymidine phosphorylase and vascular endothelial growth factor in patients with Stage I lung adenocarcinoma

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

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