Thymidine phosphorylase activity of platelet‐derived endothelial cell growth factor is responsible for endothelial cell mitogenicity

Finnis, C; Dodsworth, Neil; Pollitt, Charles E.; Carr, Grant; Sleep, Darrell

doi:10.1111/j.1432-1033.1993.tb17651.x

Cited by 65 publications

(36 citation statements)

References 44 publications

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“…Considering that this enzyme reduces thymidine levels in culture media, it is possible that the currently observed inhibition measured by 'H-TdR incorporation is, in a sense, artifactual. Finnis et a1 (30) reported that PD-ECGF promotes 3H-TdR incorporation into endothelial cells by reducing the thymidine levels that might otherwise be inhibitory. These observations explain the disparate effects of gliostatidPD-ECGF: its inhibitory activity on C6 or 3T3 cells grown in thymidine-containing medium (F-10 medium, which contains about 3 mM thymidine) and its incorporation-promoting activity on endothelial cells in thymidine-free medium (DMEM).…”

Section: Discussionmentioning

confidence: 99%

Aberrant production of gliostatin/platelet‐derived endothelial cell growth factor in rheumatoid synovium

Takeuchi

Otsuka

Matsui

et al. 1994

Arthritis & Rheumatism

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Objective. To purify a protein inhibitor from rheumatoid arthritis (RA) synovial fluids which suppresses the apparent incorporation of 3H-thymidine into fibroblasts and synovial cells, and to define its biochemical features that have clinical relevance to the pathogenesis of RA.Methods. Several standard chromatographic techniques were employed for the purification of the protein. Immunochemical methods with monoclonal antibody were used to quantify and visualize the protein in sera, synovial fluids, and tissues from RA patients.Results. The chemical properties of purified inhibitor from RA synovial fluids confirmed its identity as gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF), a potent angiogenic factor. The gliostatinl PD-ECGF level in synovial fluid and serum was higher in RA patients than in osteoarthritis controls.

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Section: Discussionmentioning

confidence: 99%

Aberrant production of gliostatin/platelet‐derived endothelial cell growth factor in rheumatoid synovium

Takeuchi

Otsuka

Matsui

et al. 1994

Arthritis & Rheumatism

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“…dThdPase is an enzyme specifically involved in the reversible dephosphorylation of thymidine to thymine and 2-deoxyribose-1-phosphate (Zimmerman and Sidenberg, 1964). The optimum pH for this activity was found to be 5.3 (Finnis et al, 1993). Site-directed mutagenesis of the PD-ECGF gene subsequently transfected into COS cells has shown that the enzymatic activity is essential to the angiogenic activity of PD-ECGF/dThdPase (Miyadera et al, 1995).…”

Section: Thymidine Phosphorylase Activitymentioning

confidence: 99%

“…PD-ECGF/dThdPase may promote angiogenesis by reducing thymidine levels inhibitory to endothelial proliferation because of the use of the thymidine salvage pathway when intracellular thymidine pools are depleted (Finnis et al, 1993), or alternatively the enzymatic products of PD-ECGF/dThdPase, namely thymine (Haraguchi et al, 1994). Studies on murine (liver), and human (placental and liver) PD-ECGF/dThdPase have shown interand intraspecies differences in substrate specificities for natural and 5-fluoropyrimidine compounds and have suggested that the hydrophobicity of the human enzymes when measured at pH 8 (not the optimum, Finnis et al, 1993) are different from their murine counterparts (Elkouni et al, 1993).…”

Section: Thymidine Phosphorylase Activitymentioning

confidence: 99%

“…Studies on murine (liver), and human (placental and liver) PD-ECGF/dThdPase have shown interand intraspecies differences in substrate specificities for natural and 5-fluoropyrimidine compounds and have suggested that the hydrophobicity of the human enzymes when measured at pH 8 (not the optimum, Finnis et al, 1993) are different from their murine counterparts (Elkouni et al, 1993).…”

Section: Thymidine Phosphorylase Activitymentioning

confidence: 99%

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Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy

Griffiths

Stratford²

1997

Br J Cancer

103

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Summary Angiogenesis plays an important role in the growth and metastasis of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to be chemotactic for endothelial cells in vitro and angiogenic in vivo. It is also known as gliostatin, a factor promoting neuronal survival, and thymidine phosphorylase (dThdPase), which catalyses the reversible phosphorylation of thymidine to thymine and 2-deoxyribose-1-phosphate. This enzymatic activity is critical for angiogenic activity. PD-ECGF protein is highly expressed in tumours compared with most normal tissues and has been correlated with tumour growth, invasion and metastasis in clinical studies. In addition, dThdPase activity (by inference PD-ECGF) has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are extensively studied clinically as anti-cancer agents. This review attempts to summarize recent gains in understanding the nature, location and action of PD-ECGF and its specific relevance to tumour biology.

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“…It was reported as both chemotactic and mitogenic for endothelial cells and angiogenic in several model systems (Ishikawa et al, 1989;Haraguchi et al, 1994;Moghaddam et al, 1995). However, recently PD-ECGF has been shown to be thymidine phosphorylase (TP) (Barton et al, 1992;Furukawa et al, 1992;Moghaddam and Bicknell, 1992;Usuki et al, 1992;Finnis et al, 1993;Sumizawa et al, 1993). TP catalyses the reversible phosphorolysis of thymidine to deoxyribose 1-phosphate and thymine.…”

mentioning

confidence: 99%

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium

Fox

Westwood²,

Moghaddam³

et al. 1996

Br J Cancer

140

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Summary Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1 -phosphate and thymine. Although known to be generally elevated in tumours, the expression of this enzyme in breast carcinomas is unknown. Therefore, we used ribonuclease protection assays and immunohistochemistry to examine the expression of TP in 240 primary breast carcinomas. Nuclear and/or cytoplasmic TP expression was observed in the neoplastic tumour epithelium in 53% of tumours. Immunoreactivity was also often present in the stromal, inflammatory and endothelial cell elements. Although endothelial cell staining was usually focal, immunoreactivity was observed in 61 % of tumours and was prominent at the tumour periphery, an area where tumour angiogenesis is most active. Tumour cell TP expression was significantly inversely correlated with grade (P = 0.05) and size (P = 0.003) but no association was observed with other tumour variables. These findings suggest that TP is important for remodelling the existing vasculature early in tumour development, consistent with its chemotactic non-mitogenic properties, and that additional angiogenic factors are more important for other angiogenic processes like endothelial cell proliferation. Relapse-free survival was higher in node-positive patients with elevated TP (P = 0.05) but not in other patient groups. This might be due to the potentiation of chemotherapeutic agents like methotrexate by TP. Therefore, this enzyme might be a prediction marker for response to chemotherapy.

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Thymidine phosphorylase activity of platelet‐derived endothelial cell growth factor is responsible for endothelial cell mitogenicity

Cited by 65 publications

References 44 publications

Aberrant production of gliostatin/platelet‐derived endothelial cell growth factor in rheumatoid synovium

Aberrant production of gliostatin/platelet‐derived endothelial cell growth factor in rheumatoid synovium

Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium

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