33 research outputs found
The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen
Introduction: The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.Methods: The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.Results: PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.Conclusions: Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets. © 2011 Fox et al.; licensee BioMed Central Ltd
Rosiglitazone and bezafibrate modulate gene expression in a rat model of non-alcoholic fatty liver disease - A historical prospective
Species-specific regulation of angiogenesis by glucocorticoids reveals contrasting effects on inflammatory and angiogenic pathways
<div><p>Glucocorticoids are potent inhibitors of angiogenesis in the rodent <i>in vivo</i> and <i>in vitro</i> but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.</p></div
Basement Membrane Biosynthesis as a Target for Developing Inhibitors of Angiogenesis with Antitumor Activity
INHIBITION OF ANGIOGENESIS, TUMOR-GROWTH AND METASTASIS BY THE NO-RELEASING VASODILATORS, ISOSORBIDE MONONITRATE AND DINITRATE
1 The effect of the nitric oxide (NO)-producing nitrovasodilators
isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were
assessed on (a) the in vivo model of angiogenesis of the chick
chorioallantoic membrane (CAM) and (b) on the growth and metastatic
properties of the Lewis Lung carcinoma (LLC) in mice.
2 Isosorbide 5-mononitrate (ISMN) and isosorbide dinitrate (ISDN),
inhibited angiogenesis in the CAM dose-dependently. ISMN was more potent
in inhibiting this process. Both compounds were capable of completely
reversing the angiogenic effect of alpha-thrombin. These effects of ISMN
and ISDN on angiogenesis were comparable to those previously observed
with sodium nitroprusside which generates NO non-enzymatically.
3 Mice, implanted intramuscularly with LLC, received daily i.p.
injections of ISMN for 14 days resulting in a significant decrease in
the size of the primary tumour and a reduction in the number and size of
metastatic foci in the lungs. ISDN had a similar but less pronounced
effect than that observed with ISMN.
4 Addition of ISMN or ISDN to cultures of bovine, rabbit and human
endothelial cells and to cultures of LLC cells had no effect on their
growth characteristics.
5 These results indicate that ISMN and ISDN inhibit angiogenesis and
tumour growth and metastasis in an animal tumour model. The possibility
should therefore be considered that these nitrovasodilators which are
widely used therapeutically and have well characterized pharmacological
profiles, may also possess antitumour properties in the clinic