Angiogenic activity of enzymes

Haraguchi, Masanobu; Miyadera, Kazutaka; Uemura, K; Sumizawa, Tomoyuki; Furukawa, Tatsuhiko; Yamada, Kazutaka; Akiyama, Shin–ichi; Yamada, Yuji

doi:10.1038/368198a0

Cited by 321 publications

(208 citation statements)

References 10 publications

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“…For long-term angiogenesis studies the postimplantation time must be extended to determine the effect of a potentially antiangiogenic treatment. Regarding these studies it may be interesting to investigate TAS-102 with respect to inhibition of blood vessel formation in tumours since TPI also inhibits PD-ECGF, which is considered to be proangiogenic (Haraguchi et al, 1994). We observed after 10-days treatment with TAS-102 that TPI acts as an antiangiogenic compound (as previously shown (Matsushita et al, 1999;Emura et al, 2005)) and is likely to be related to the suppression of metastasis (Takao et al, 2000;Sato et al, 2003).…”

Section: Discussionsupporting

confidence: 69%

The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells

et al. 2006

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The Hollow Fibre Assay (HFA) is usually applied as an early in vivo model for anti-cancer drug screening, but is potentially an excellent model for short-term in vivo pharmacodynamic studies. We used the model to study the in vivo role of thymidine phosphorylase/ platelet-derived endothelial cell growth factor (TP/PD-ECGF) in the cytotoxicity and pharmacodynamics of TAS-102 in colon cancer cells. TAS-102 is a new oral drug formulation, which is composed of trifluorothymidine (TFT) and thymidine phosphorylase inhibitor (TPI), which prevents TFT degradation. We compared the activity with Xeloda (capecitabine), which is activated by TP into 5FU. Hollow fibres filled with human Colo320 or Colo320TP1 colorectal cancer cells with deficient or high TP expression, respectively, were implanted subcutaneously (s.c.) at both flanks of BALB/c mice. The mice were treated orally over 5 days with TAS-102, TFT alone, 5 0 DFUR7TPI or capecitabine at their maximum tolerated dose (MTD). The cells were retrieved from the fibres and assayed for growth (MTT assay), cell cycle distribution (flow cytometry) and apoptosis induction (FragEL method). TAS-102 induced considerable growth inhibition (50%, Po0.01) to both cell lines, which was completely abolished in the absence of TPI. Capecitabine and its metabolite 5 0 DFUR reduced proliferation of Colo320TP1 cells in the fibres significantly (down to 25 -40%), but much less in Colo320 cells, whereas addition of TPI reduced the effect of 5 0 DFUR, although not completely. These differences in cytotoxic effects were reflected in the pharmacodynamic evaluation. TAS-102 induced a G2M-phase arrest (from 25 to 40%) and apoptosis (48-fold), which was more pronounced in Colo320 than in Colo320TP1. Again, omission of TPI neutralised the effect of TAS-102. Similarly, 5 0 DFUR and capecitabine induced a significant G2M-phase arrest (up to 45%) in the Colo320TP1 cell line, but less pronounced in the parental Colo320. Addition of TPI to 5 0 DFUR reduced this effect to control levels. Also induction of apoptosis was reduced in the presence of TPI. The data demonstrated that the HFA is excellently suited for studying short-term pharmacodynamic effects of fluoropyrimidines in vivo. TAS-102 is only effective in inducing cytotoxicity when systemic TPI is present, but acts against both low and high TP expressing colon cancer cells, while 5 0 DFUR needs cellular TP to exert significant activity.

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Section: Discussionsupporting

confidence: 69%

The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells

et al. 2006

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“…The enzymatic activity of TP is indispensable for the angiogenic effect, since a competitive inhibitor of TP could block the angiogenic effect [18]. Therefore, substrate and metabolites from the reaction are often used for studying the angiogenic effect of TP [19].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells

Bijnsdorp

Azijli

Jansen

et al. 2010

Biochemical Pharmacology

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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).…”

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confidence: 99%

“…TP is not a classic growth factor and the mechanism by which TP promotes angiogenesis is unknown. Nevertheless, some evidence suggests that metabolites of TP might be responsible for its angiogenic activity (Morris et al, 1989;Moghaddam and Bicknell, 1992;Haraguchi et al, 1994).…”

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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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Angiogenic activity of enzymes

Cited by 321 publications

References 10 publications

The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells

The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells

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

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