HER2 Support Group Forums - View Single Post - Surgeons/anaesthesiologists should avoidgiving opiates (morphine) to cancer patients

Rich66 · 11-19-2009, 03:23 PM

Looks like the researchers filed for a related patent last year.

Patrick A. Singleton

CHICAGO, IL US

1. 20080274119 Use of Opioid Antagonists to Attenuate Endothelial Cell Proliferation and Migration 11-06-2008

[0056]The present invention provides methods of attenuating abnormal or undesirable migration and/or proliferation of endothelial cells. As such, the invention provides methods for attenuating angiogenesis in a tissue or an organ of a subject by the use of opioid antagonists, and a novel approach for treating angiogenic related diseases and other hyperproliferative diseases in mammals. For example, as described above, solid tumors rely on the generation of new blood vessels for nutrients to reach the cells within the tumor. The growth factors required for angiogenesis can be produced by the tumor cells or alternatively, exogenous factors, such as opioids can stimulate new blood vessel growth. The present invention by the use of opioid antagonists provides a novel therapeutic approach to the treatment of such tumors, wherein the generation of new blood vessels within the tumor, rather than the tumor cells themselves, is the target. This treatment is not likely to lead to the development of resistant tumor cells.

[0057]Described herein are opioid antagonists inhibit proliferation and migration induced by opioids, endogenous or exogenous, and growth factors, such as VEGF, PDGF, S1P etc. Peripheral opioid antagonists, in particular, showed a substantial efficacy in inhibiting opioid and growth factor induced proliferation and migration of endothelial cells. The peripheral opioid antagonist methylnaltrexone (MNTX) inhibited both opioid and growth factor induced proliferation and migration in a concentration dependent manner. In addition, naloxone also inhibited opioid-induced endothelial migration. It should be noted, however, that the naloxone inhibition of DAMGO induced migration of endothelial cells occurred at a relatively high, micromolar, concentration of naloxone. Furthermore, it has now been discovered that opioid antagonists, and the peripheral opioid antagonist MNTX in particular, inhibit agonist induced endothelial cell (EC) proliferation and migration via inhibition of receptor phosphorylation and/or transactivation and subsequent inhibition of RhoA activation. The agonists can be opioids, exogenous and/or endogenous, angiogenic factors (VEGF), and other proliferation and/or migration stimulating factors (PDGF, S1P, S1P3 receptor, RhoA, etc). These results suggest that inhibition of angiogenesis by opioid antagonists can be a useful therapeutic intervention for, among other disorders, cancer.

Ok..MNTX is different than regular ole naltrexone
Abstract

Methylnaltrexone potentiates the antiangiogenic effects of the mTOR inhibitor, temsirolimus

P. A. Singleton, J. Moss and J. G. Garcia University of Chicago, Chicago, IL
e14636
Background: Angiogenesis is important in cancer growth and metastasis. Recent therapeutic interventions cancer, include drugs such as temsirolimus that target both tumor growth and angiogenesis including the mammalian target of rapamycin (mTOR) inhibitor. Previously, we have demonstrated that the peripheral opioid antagonist methylnaltrexone (MNTX) potentiates the effects of bevacizumab and 5FU on endothelial cell (EC) migration and proliferation. Since mTOR inhibitor therapy is also associated with significant side effects, we examined potential adjunctive agents that could reduce the therapeutic dose and improve the therapeutic window for this approach. Methods: We determined the effect(s) of MNTX, naloxone and/or temsirolimus on VEGF-induced human pulmonary microvascular EC proliferation and migration assays. We used siRNA and specific inhibitors to analyze Src, Akt and mTOR regulation. Results: MNTX inhibited EC VEGF-induced proliferation and migration with an IC50 of

100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation from

10 nM to

1 nM. Further, adding 10 nM MNTX shifted the IC50 of temsirolimus on inhibition of EC migration from

50 nM to

10 nM. These synergistic effects were not observed with naltrexone, a tertiary mu opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased protein tyrosine phosphatase (PTP) activity which was independent of mu opioid receptor expression. Treatment of human EC with the PTP inhibitor, 3,4-Dephostatin, inhibited both the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR complex 1 (temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. Conclusions: Synergy of MNTX with mTOR inhibitors may have therapeutic implications which await clinical proof-of-concept.

Anticancer Res. 2009 Aug;29(8):2927-32.
Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells.

Wang CZ, Li XL, Sun S, Xie JT, Aung HH, Tong R, McEntee E, Yuan CS.
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.
BACKGROUND: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. MATERIALS AND METHODS: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. RESULTS: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A. CONCLUSION: At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.

PMID: 19661297 [PubMed - indexed for MEDLINE]

11-19-2009, 03:23 PM	#4
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Surgeons/anaesthesiologists should avoidgiving opiates (morphine) to cancer patie Looks like the researchers filed for a related patent last year. Patrick A. Singleton CHICAGO, IL US 1. 20080274119 Use of Opioid Antagonists to Attenuate Endothelial Cell Proliferation and Migration 11-06-2008 [0056]The present invention provides methods of attenuating abnormal or undesirable migration and/or proliferation of endothelial cells. As such, the invention provides methods for attenuating angiogenesis in a tissue or an organ of a subject by the use of opioid antagonists, and a novel approach for treating angiogenic related diseases and other hyperproliferative diseases in mammals. For example, as described above, solid tumors rely on the generation of new blood vessels for nutrients to reach the cells within the tumor. The growth factors required for angiogenesis can be produced by the tumor cells or alternatively, exogenous factors, such as opioids can stimulate new blood vessel growth. The present invention by the use of opioid antagonists provides a novel therapeutic approach to the treatment of such tumors, wherein the generation of new blood vessels within the tumor, rather than the tumor cells themselves, is the target. This treatment is not likely to lead to the development of resistant tumor cells. [0057]Described herein are opioid antagonists inhibit proliferation and migration induced by opioids, endogenous or exogenous, and growth factors, such as VEGF, PDGF, S1P etc. Peripheral opioid antagonists, in particular, showed a substantial efficacy in inhibiting opioid and growth factor induced proliferation and migration of endothelial cells. The peripheral opioid antagonist methylnaltrexone (MNTX) inhibited both opioid and growth factor induced proliferation and migration in a concentration dependent manner. In addition, naloxone also inhibited opioid-induced endothelial migration. It should be noted, however, that the naloxone inhibition of DAMGO induced migration of endothelial cells occurred at a relatively high, micromolar, concentration of naloxone. Furthermore, it has now been discovered that opioid antagonists, and the peripheral opioid antagonist MNTX in particular, inhibit agonist induced endothelial cell (EC) proliferation and migration via inhibition of receptor phosphorylation and/or transactivation and subsequent inhibition of RhoA activation. The agonists can be opioids, exogenous and/or endogenous, angiogenic factors (VEGF), and other proliferation and/or migration stimulating factors (PDGF, S1P, S1P3 receptor, RhoA, etc). These results suggest that inhibition of angiogenesis by opioid antagonists can be a useful therapeutic intervention for, among other disorders, cancer. Ok..MNTX is different than regular ole naltrexone Abstract Methylnaltrexone potentiates the antiangiogenic effects of the mTOR inhibitor, temsirolimus P. A. Singleton, J. Moss and J. G. Garcia University of Chicago, Chicago, IL e14636 Background: Angiogenesis is important in cancer growth and metastasis. Recent therapeutic interventions cancer, include drugs such as temsirolimus that target both tumor growth and angiogenesis including the mammalian target of rapamycin (mTOR) inhibitor. Previously, we have demonstrated that the peripheral opioid antagonist methylnaltrexone (MNTX) potentiates the effects of bevacizumab and 5FU on endothelial cell (EC) migration and proliferation. Since mTOR inhibitor therapy is also associated with significant side effects, we examined potential adjunctive agents that could reduce the therapeutic dose and improve the therapeutic window for this approach. Methods: We determined the effect(s) of MNTX, naloxone and/or temsirolimus on VEGF-induced human pulmonary microvascular EC proliferation and migration assays. We used siRNA and specific inhibitors to analyze Src, Akt and mTOR regulation. Results: MNTX inhibited EC VEGF-induced proliferation and migration with an IC50 of 100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation from 10 nM to 1 nM. Further, adding 10 nM MNTX shifted the IC50 of temsirolimus on inhibition of EC migration from 50 nM to 10 nM. These synergistic effects were not observed with naltrexone, a tertiary mu opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased protein tyrosine phosphatase (PTP) activity which was independent of mu opioid receptor expression. Treatment of human EC with the PTP inhibitor, 3,4-Dephostatin, inhibited both the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR complex 1 (temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. Conclusions: Synergy of MNTX with mTOR inhibitors may have therapeutic implications which await clinical proof-of-concept. Anticancer Res. 2009 Aug;29(8):2927-32. Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells. Wang CZ, Li XL, Sun S, Xie JT, Aung HH, Tong R, McEntee E, Yuan CS. Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA. BACKGROUND: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. MATERIALS AND METHODS: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. RESULTS: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A. CONCLUSION: At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents. PMID: 19661297 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)