1 Thymidine phosphorylase (TP) is elevated in the plasma of cancer patients, and has been implicated in pathophysiological angiogenesis. However, the downstream signals underlying this implication remain obscure. The purpose of the present study was to examine the effects of TP on the neovascularisation response in vitro and in vivo. 2 Both TP and its catalytic product, 2-deoxy-D-ribose-1-phosphate, and downstream 2-deoxy-Dribose (2-DDR) promoted endothelial tubulogenesis in vitro, and the regeneration of a wounded monolayer of endothelial cells without exerting any mitogenic effect. In vivo, both TP and 2-DDR promoted the development of functional vasculature into an avascular sponge. A TP inhibitor, 6-amino-5-chlorouracil, was able to partially reverse the effects of TP, but had no effect on the 2-DDRinduced angiogenesis. 3 Enhanced monolayer regeneration was observed with TP-cDNA-transfected bladder carcinoma cells. The transfection of TP-cDNA, however, did not confer any proliferative advantage. The regeneration of TP overexpressing cells was associated with a time-dependent expression of the enzyme haeme-oxygenase (HO-1). 4 The present study demonstrates that both TP and its ribose-sugar metabolites induce angiogenesis by mediating a cohesive interplay between carcinoma and endothelial cells. The induction of HO-1 in TP-transfected cells suggests that it could be a possible downstream signal for the angiogenic effects of TP. Furthermore, reducing sugars have been shown to induce oxidative stress, and ribose could be a possible cause for the upregulation of HO-1, which has been implicated in the release of angiogenic factors. Therefore, we postulate that 2-DDR could be mediating the angiogenic effects of TP possibly through an oxidative stress mechanism and additionally getting integrated in the endothelial metabolic machinery. British Journal of Pharmacology (2003) 139, 219-231. doi:10.1038/sj.bjp.0705216 Keywords: Thymidine phosphorylase; deoxy-D-Ribose; haemeoxygenase-1; angiogenesis Abbreviations: TP, thymidine phosphorylase; 2-DDR, 2-deoxy-D-ribose; 2-DLR, 2-deoxy-L-ribose; HO1, haemeoxygenase-1; TP inhibitor, 6-amino-5-chlorouracil; VEGF, vascular endothelial growth factor; CO, carbon monoxide; EBM, endothelial basal medium; EGM, endothelial growth medium IntroductionAngiogenesis or neovascularisation is finely choreographed through the interplay of the endothelial cells, angiogenic mediators, cytokines, growth factors and adhesion molecules, and can be said to involve three key events, namely migration, proliferation and maturation of the endothelial cells (Griffioen & Molema, 2000). Angiogenesis is of fundamental importance in several physiological processes including embryogenesis, wound healing and the menstrual cycle. It is however also implicated in certain pathological conditions, such as atherosclerosis, diabetic retinopathy, psoriasis and tumour growth (Griffioen & Molema, 2000). Thymidine phosphorylase (TP), which is identical to platelet-derived endothelial cell growth factor (Furukawa et a...

Bile acid composition, synthetic rate and pool size were determined in rats fed diets containing 5 g cellulose, 5 g pectin or 5 g psyllium hydrocolloid/100 g diet using the washout technique. Bile acid pool sizes were similar for pectin- and psyllium-fed rats, and both were higher than the pool size for rats fed cellulose (5.48 +/- 1.22, 4.70 +/- 0.71 and 1.77 +/- 0.41 mumol/100 g body wt, respectively). Bile acid secretion rates showed a similar pattern [1730 +/- 496, 1551 +/- 252 and 572 +/- 88 nmol/(h.100 g body wt)], as did basal synthetic rates [129 +/- 25, 126 +/- 42 and 87 +/- 18 pmol/(h.100 g body wt)]. Individual and total bile acid pool sizes were generally higher in animals fed the pectin- or psyllium-supplemented diet compared with rats fed cellulose. Pectin or psyllium consumption resulted in a lower hydrophobicity of the bile acid pool and a lower ratio of circulating 12 alpha-hydroxylated to non-12 alpha-hydroxylated bile acids compared with cellulose consumption. This reduced hydrophobicity has been shown to reduce feedback inhibition of bile acid synthesis and may be responsible for the larger bile acid pool size. Changes in the location of reabsorption of bile acids may also be responsible for changes in the pool size and composition. These changes are characteristic of greater sterol excretion.

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. Can. J. Chem. 53, 826 (1975).The rates of formation of hydroxy-9,lO-anthraquinone-2-sulfonates, produced by irradiationof neutral and alkaline aqueous solutions of 9,lO-anthraquinone-2-sulfonate (A) at 365 nm, have been measured for solutions with initial [A] rangingfrom 5 x to 8 x m~l d m -~, saturated with either 02, air, or Nz. The rate of monohydroxylation was independent of the saturating gas and, for neutral solutions absorbing all the incident light, increased with increasing initial [A] reaching a constant maximum quantum yield of 0.08 above 2 x rnol dm-J. In 0.1 mol dm-J aqueous NaOH solution, the rate was about three times largerbut had not attained a limiting value at the maximum a 8 x mol dm-', saturees soit en 0,, en air ou en N2, les vitesses de formation des hydroxyanthraq~~inone-9,10 sulfonates-2 produits par irradiation de solutions aqueuses, neutres ou alcalines d'anthraquinone-9.10 sulfonate-2 (A). Le taux de monohydroxylation est independant du gaz produisant la saturation et dans des solutions neutres absorbant toute la lumikre incidente, la vitesse augmente avec I'augmentation de la vitesse initiale de [A] approchant un rendement quantique maximum constant de 0.08 au dessus de 2 x mol dm-J. Dans des solutions aqueuses de NaOH aO.l mol dm-j, la vitesse est environ trois fois plus grande mais elle n'avait pas atteint une valeur limite a la concentration maximum de [A] imposee par sa solubilitk. On propose que les dihydroxyanthraquinone-9,10 sulfonates se forment par reaction de 0 2 avec un intermediaire plut6t que par une hydroxylation ulterieure des produits monohydroxyles. Le taux de dihydroxylation diminue lorsque la concentration de [A] augmente au dessus de 5 x mol dm-' et cette vitesse devient pratiquement zero a haute concentration.[Traduit par le journal]

To further understand the molecular mechanisms of bile acid-mediated colon tumor promotion, we have examined the possible role of AP-1 activity in this process. The AP-1 complex has been reported to play an important role in control of cell growth. Our studies show that lithocholate, deoxycholate and ursodeoxycholate exhibited marked proliferative effects on a human adenocarcinoma cell line (HT29), while cholate was without effect. The proliferative effects appeared to be confined to narrow concentration windows which differed for the different bile acids. We demonstrate that deoxycholate caused an increase in expression of c-fos mRNA and increased binding to the AP-1 site, effects which were maximum at the concentration at which the bile acid induced the maximum proliferative effect on the cells. Cholate was without effect on AP-1 binding activity. In addition, we show that the AP-1 complex induced by treatment of the cells with the bile acid contained the c-fos protein. This could suggest that prolonged deregulated expression of AP-1 activity in colonic cells by certain bile acids may contribute to tumor promotion in the colon.