Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression.
Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.).
The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49-81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 +/- 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 +/- 2 mg/dL) decreased from 2,086 +/- 390 pg/mL to 1,250 +/- 712 pg/mL (p < 0.002) at target ceruloplasmin (13 +/- 2 mg/dL; p < 0.0001 from baseline). The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non-TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months).
Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy.
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"Indeed, we now have preliminary data showing that combining copper depletion treatment with cisplatin is antagonistic (data not shown). The only clinical trial in mesothelioma patients reported to-date was a combination therapy in which TM therapy was given post surgery, and the data showed that the time to disease progression was slowed by 10 months . As the current survival time for patients with mesothelioma is 12 months post diagnosis any therapy that increases survival time could make a considerable difference in the lives of these patients. "
[Show abstract][Hide abstract] ABSTRACT: Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.
"Results indicate that a wide repertoire of chemokines (CXC-ELR+ and CC-chemokines) may drive the neoangiogenesis induced by the cooperative effects of cancer cells and Mφ. Finally, tetrathiomolybdate (TM), an oral copper-depleting agent that has been shown to inhibit tumour-cell-induced angiogenesis [25-27] was tested in our model of cooperation between Mφ and MDA-MB-231. This was important to check because the effect of TM has not previously been analysed in this context of inflammation in cancers. "
[Show abstract][Hide abstract] ABSTRACT: Infiltration by macrophages (Mphi) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mphi and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity.
Mphi coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mphi phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor alpha (TNFalpha) when stimulated by lipopolysaccharide/interferon gamma (LPS/IFNgamma); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mphi and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM.
Incubation of Mphi with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mphi to switch from M1 Mphi towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNgamma stimulation, an increased secretion of IL-10, a decreased secretion of TNFalpha in response to LPS/IFNgamma and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines.
Cooperation between Mphi and MDA-MB-231 transformed M1 Mphi to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mphi phenotype or cytokine secretion profiles.
[Show abstract][Hide abstract] ABSTRACT: Graduation date: 2010 Endothelial activation with increased expression of cellular adhesion molecules, chemokines and pro-inflammatory cytokines critically contributes to vascular inflammation and the initiation and progression of atherosclerosis. By affecting redox-sensitive cell signaling pathways and transcription factors, redox-active transition metal ions, such as copper and iron, may play an important role in these processes. The goals of my studies were to investigate the role of copper in systemic and vascular inflammation, endothelial activation, and atherosclerotic lesion development, using tetrathiomolybdate (TTM), a clinically-used copper chelator, as a specific means to manipulate cellular copper levels in vitro and in vivo. Incubation of human aortic endothelial cells (HAEC) with copper induced activation of the redox-sensitive transcription factors, nuclear factor kappa B (NF-kB) and activator protein-1 (AP-1) and up-regulation of mRNA and protein levels of adhesion molecules and the chemokine, monocyte chemotactic protein-1 (MCP-1), in a dose- and time-dependent manner. Furthermore, TTM inhibited TNFa-induced increases of mRNA and protein levels of adhesion molecules and MCP-1 in a dose-dependent manner. TNFa-induced activation of NF-kB and AP-1 also was dose-dependently attenuated by TTM, and inhibition of NF-kB activity was associated with decreased phosphorylation and degradation of its cytosolic inhibitory subunit, IkBa. In an in vivo model of systemic inflammation using of C57BL mice, oral TTM administration for three weeks significantly reduced bioavailable copper and inhibited lipopolysaccharide (LPS)-induced upregulation of inflammatory gene expression in aorta and heart. Tetrathiomolybdate also significantly inhibited LPS-induced increases of serum levels of soluble adhesion molecules, MCP-1, and pro-inflammatory cytokines. Similar inhibitory effects of TTM were observed on NF-kB and AP-1 activation in the heart and lungs. In apolipoprotein E-deficient (apoE-/-) mice, a well established animal model of human atherosclerosis, dietary supplementation with TTM for ten weeks significantly reduced bioavailable copper and attenuated atherosclerotic lesion development, which was particularly pronounced in the descending aorta. This anti-atherogenic outcome of TTM supplementation was accompanied by several anti-inflammatory effects, such as significantly declined serum levels of soluble adhesion molecules, reduced aortic gene expression of inflammatory mediators, and less aortic macrophage accumulation. Importantly, TTM supplementation for ten weeks did not cause liver toxicity or anemia. In conclusion, my studies provide the proof of concept that copper plays an important role in systemic and vascular inflammation and the pathogenesis of atherosclerosis, and demonstrate that tetrathiomolybdate exerts anti-inflammatory and anti-atherogenic effects in preclinical animal models. The possible implications of these findings for cardiovascular and inflammatory diseases in humans remain to be investigated.