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Eugenie S Kleinerman - One of the best experts on this subject based on the ideXlab platform.
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addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma a report from the children s oncology group
Cancer, 2009Co-Authors: Alexander Jaho Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Ernest U Conrad, Michael L Nieder, Michael A Weiner, Zhengjia Chen, Robert J WellsAbstract:BACKGROUND: The addition of liposomal Muramyl Tripeptide phosphatidylethanolamine (MTP-PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP-PE to chemotherapy for patients with metastatic OS. METHODS: Intergroup-0133 was a prospective randomized phase 3 trial for the treatment of newly diagnosed patients with OS. The authors compared 3-drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same 3 drugs with the addition of ifosfamide (Regimen B). The addition of liposomal MTP-PE to chemotherapy was evaluated. RESULTS: Five-year event-free survival (EFS) for patients who received liposomal MTP-PE (n = 46) was 42% versus 26% for those who did not (n = 45) (relative risk for liposomal MTP-PE, 0.72; P = .23; 95% confidence interval [CI], 0.42-1.2). The 5-year overall survival for patients who received MTP-PE versus no MTP-PE was 53% and 40%, respectively (relative risk for liposomal MTP-PE, 0.72; P = 0.27; 95% CI, 0.40-1.3). The comparison of Regimen A with Regimen B did not suggest a difference for EFS (35% vs 34%, respectively; relative risk for Regimen B, 1.07; P = .79; 95% CI, 0.62-1.8) or overall survival (52% vs 43%, respectively; relative risk for Regimen B, 1.1, P = .75; 95% CI, 0.61-2.0). CONCLUSIONS: When the metastatic cohort was considered in isolation, the addition of liposomal MTP-PE to chemotherapy did not achieve a statistically significant improvement in outcome. However, the pattern of outcome is similar to the pattern in nonmetastatic patients. Cancer 2009. © 2009 American Cancer Society.
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addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma a report from the children s oncology group
Journal of Clinical Oncology, 2008Co-Authors: Alexander J Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Helen Nadel, Michael L Nieder, Michael A Weiner, Robert J Wells, Paul A MeyersAbstract:10018 Background: With longer followup, the addition of Muramyl Tripeptide (MTP) to chemotherapy has been shown to improve overall survival in patients with non-metastatic osteosarcoma (OS). We rep...
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Addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group
Journal of Clinical Oncology, 2008Co-Authors: Alexander J Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Helen Nadel, Michael L Nieder, Michael A Weiner, Robert J Wells, Paul A MeyersAbstract:10018 Background: With longer followup, the addition of Muramyl Tripeptide (MTP) to chemotherapy has been shown to improve overall survival in patients with non-metastatic osteosarcoma (OS). We report the results of MTP addition to chemotherapy for patients with metastatic OS. Methods: Intergroup-0133 was a prospective randomized trial for the treatment of newly diagnosed patients with OS. We compared three drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same three drugs with the addition of ifosfamide (Regimen B). We evaluated the addition of MTP to chemotherapy. We report herein the first analysis of 91 patients with metastatic OS at presentation. Outcome measures included event free survival (EFS) and survival. Results: Five-year EFS for patients who received MTP (n=46) was 42% versus 26% for those who did not (n=45), p=0.38. The 5-year overall survival for patients who received MTP versus no MTP was 53% and 40% respectively (p=0.36). The comparison of Regim...
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osteosarcoma a randomized prospective trial of the addition of ifosfamide and or Muramyl Tripeptide to cisplatin doxorubicin and high dose methotrexate
Journal of Clinical Oncology, 2005Co-Authors: Paul A Meyers, Cindy L Schwartz, Mark Krailo, Mark L Bernstein, Donna L Betcher, Mark C Gebhardt, Eugenie S Kleinerman, Ernest U Conrad, William S Ferguson, Allen M GoorinAbstract:Purpose To determine whether the addition of ifosfamide and/or Muramyl Tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Patients and Methods Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 × 2 factorial design. The primary end point for analysis was EFS. Results Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition ...
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Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2005Co-Authors: Paul A Meyers, Cindy L Schwartz, Mark Krailo, Mark L Bernstein, Donna L Betcher, William Ferguson, Mark C Gebhardt, Eugenie S Kleinerman, Ernest U Conrad, Allen M GoorinAbstract:Purpose To determine whether the addition of ifosfamide and/or Muramyl Tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Patients and Methods Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 × 2 factorial design. The primary end point for analysis was EFS. Results Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition ...
Paul A Meyers - One of the best experts on this subject based on the ideXlab platform.
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Muramyl Tripeptide-Phosphatidyl Ethanolamine Encapsulated in Liposomes (L-MTP-PE) in the Treatment of Osteosarcoma.
Advances in experimental medicine and biology, 2020Co-Authors: Paul A MeyersAbstract:The recruitment of autologous macrophages to attack osteosarcoma represents a novel immunotherapy approach to the treatment of osteosarcoma. Muramyl Tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) was derived as a compound with the ability to stimulate macrophages to destroy autologous osteosarcoma tumor cells. Preclinical studies including studies in dogs with spontaneously arising osteosarcoma showed the ability of L-MTP-PE to control microscopic metastatic disease in osteosarcoma. A pivotal clinical trial led to the approval of L-MTP-PE for the treatment of newly diagnosed osteosarcoma in over 40 countries.
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Muramyl Tripeptide phosphatidyl ethanolamine encapsulated in liposomes l mtp pe in the treatment of osteosarcoma
Advances in Experimental Medicine and Biology, 2014Co-Authors: Paul A Meyers, Alexander Jaho ChouAbstract:Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified Muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in Muramyl Tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal Muramyl Tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.
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Muramyl Tripeptide mifamurtide for the treatment of osteosarcoma
Expert Review of Anticancer Therapy, 2009Co-Authors: Paul A MeyersAbstract:Osteosarcoma is an ultraorphan disease. There are approximately 1000 new patients diagnosed with osteosarcoma each year in the USA and Europe. Current treatment for osteosarcoma utilizes multiagent chemotherapy and surgical resection of all clinically detectable disease. Current treatments for osteosarcoma achieve 60–70% event-free survival (EFS) for patients with localized disease and approximately 20% EFS for patients who present with metastasis. These results have been stable for two decades. The addition of Muramyl Tripeptide (mifamurtide) to chemotherapy resulted in a trend towards improved EFS and a one-third reduction in the risk of death from osteosarcoma. Mifamurtide has been approved in Europe for the treatment of newly diagnosed osteosarcoma in combination with chemotherapy.
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addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma a report from the children s oncology group
Journal of Clinical Oncology, 2008Co-Authors: Alexander J Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Helen Nadel, Michael L Nieder, Michael A Weiner, Robert J Wells, Paul A MeyersAbstract:10018 Background: With longer followup, the addition of Muramyl Tripeptide (MTP) to chemotherapy has been shown to improve overall survival in patients with non-metastatic osteosarcoma (OS). We rep...
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Addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group
Journal of Clinical Oncology, 2008Co-Authors: Alexander J Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Helen Nadel, Michael L Nieder, Michael A Weiner, Robert J Wells, Paul A MeyersAbstract:10018 Background: With longer followup, the addition of Muramyl Tripeptide (MTP) to chemotherapy has been shown to improve overall survival in patients with non-metastatic osteosarcoma (OS). We report the results of MTP addition to chemotherapy for patients with metastatic OS. Methods: Intergroup-0133 was a prospective randomized trial for the treatment of newly diagnosed patients with OS. We compared three drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same three drugs with the addition of ifosfamide (Regimen B). We evaluated the addition of MTP to chemotherapy. We report herein the first analysis of 91 patients with metastatic OS at presentation. Outcome measures included event free survival (EFS) and survival. Results: Five-year EFS for patients who received MTP (n=46) was 42% versus 26% for those who did not (n=45), p=0.38. The 5-year overall survival for patients who received MTP versus no MTP was 53% and 40% respectively (p=0.36). The comparison of Regim...
Isaiah J Fidler - One of the best experts on this subject based on the ideXlab platform.
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Maintenance of Intestinal Epithelium Structural Integrity and Mucosal Leukocytes During Chemotherapy by Oral Administration of Muramyl Tripeptide Phosphatidylethanolamine
Cancer biotherapy & radiopharmaceuticals, 1996Co-Authors: Jerald J. Killion, Corazon D. Bucana, Robert Radinsky, Zhongyun Dong, Terry O'reilly, Graham Bilbe, Lajos Tarcsay, Isaiah J FidlerAbstract:The systemic administration of doxorubicin (DXR) decreases the number of epithelial cells and leukocytes in the small intestine of mice. Oral administration of Muramyl Tripeptide phosphatidylethano...
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Intravesical liposomal Muramyl Tripeptide phosphatidylethanolamine treatment of human bladder carcinoma growing in nude mice.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 1995Co-Authors: Colin P.n. Dinney, Corazon D. Bucana, Simon Tanguay, Beryl Y. Eve, Isaiah J FidlerAbstract:The present study evaluated the in vivo activity of synthetic lipophilic Muramyl Tripeptide phosphatidylethanolamine (MTP-PE) when encapsulated into liposomes (phosphatidylcholine-phosphatidylserine, 7:3 molar ratio) and administered intravesically to athymic nude mice with human transitional cell carcinoma 253J-V cells growing in their bladder. Intravesical liposome-MTP-PE was effective in eradicating the human tumors implanted orthotopically in nude mice. Following therapy, activated macrophages were found in the bladders of liposome-MTP-PE-treated mice but not in control mice. In vitro activation of murine macrophages with liposome-MTP-PE increased their cytotoxicity against the 253J-V cell line used in these experiments. This effect was enhanced by cotreatment with interferon-gamma (IFN-gamma). Furthermore, cotreatment of macrophages with both liposome-MTP-PE and IFN-gamma resulted in the secretion of both tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Liposome-encapsulated MTP-PE shows promise as an effective therapeutic agent for bladder carcinoma.
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Prevention of chemotherapy- or X-irradiation-induced monocytopenia by oral administration of lipophilic Muramyl Tripeptide.
Oncology research, 1994Co-Authors: Jerald J. Killion, Michael R. Wilson, Dale Brown, Mary Lloyd, Isaiah J FidlerAbstract:Subsequent to systemic administration of doxorubicin or whole-body X-irradiation, C57BL/6 mice exhibit a depletion in lymphoid cells (macrophages) lasting 2-3 weeks and returning to normal by 4 weeks after either treatment. We evaluated the ability of repeated oral administration of the synthetic macrophage activator Muramyl Tripeptide phosphatidylethanolamine (MTP-PE), either in free form or encapsulated into multilamellar liposomes, to reverse or prevent the decline in macrophages after cytoreductive therapies. The number of both resident peritoneal macrophages and peritoneal exudate cells elicited by thioglycollate-induced inflammation increased after the oral administration of MTP-PE (three times a week) for at least 3 weeks. The depletion of macrophage number from the peritoneal cavity that occurred after two IV injections of doxorubicin or X-irradiation with 1.5 or 3.0 Gy was prevented by repeated oral feedings of MTP-PE. Moreover pretreatment of mice with oral MTP-PE prevented depletion of macrophages resulting from IV injections of doxorubicin. Modest protection was also noted for blood leukocytes in mice receiving oral MTP-PE following systemic DXR. Similar effects were achieved when MTP-PE was encapsulated into phospholipid liposomes: this formulation also allowed macrophages to be readily activated to the tumoricidal state. The oral administration of MTP-PE offers an additional strategy for protection of host defense cells during cytoablative therapies.
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Liposomes containing Muramyl Tripeptide phosphatidylethanolamine (MTP-PE) are excellent adjuvants for induction of an immune response to protein and tumor antigens.
Journal of leukocyte biology, 1992Co-Authors: Stephen E. Ullrich, Isaiah J FidlerAbstract:Liposomes containing the synthetic lipophilic analog of Muramyl dipeptide, Muramyl Tripeptide phos- phatidylethanolamine (MTP-PE), were used as adju- vants for the induction of humoral and cellular immune responses following immunization with protein or tumor antigens. Cellular immune reactions, including delayed- type hypersensitivity and lymphoproliferation in vitro, were observed following immunization of mice with a mixture of antigen and liposome-MTP-PE. Immuniza- tion with murine melanoma K1735 cells, admixed with liposomal MTP-PE, induced a protective immune response as demonstrated by the rejection of transplanted tumor cells. Antibody production was also induced fol- lowing immunization with protein antigens admixed with liposome-MTP-PE. The efficacy of adjuvant ac- tivity following immunization with antigens admixed with liposome-MTP-PE was equal to or better than that of complete Freund's adjuvant (CFA). Moreover, liposome- MTP-PE did not have the toxic side effects associated with CFA. These data suggest that phospholipid liposomes containing MTP-PE are superior adjuvants and should receive consideration for vaccine therapy.J. Leukoc. Biol. 52: 489-494; 1992.
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Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal Muramyl Tripeptide (CGP 19835A lipid)
Cancer Immunology Immunotherapy, 1992Co-Authors: Eugenie S Kleinerman, Corazon D. Bucana, Michael B. Harris, Norman Jaffe, Austin K. Raymond, Irwin H. Krakoff, Robert Benjamin, Isaiah J FidlerAbstract:We have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m^2) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.
Irma A. J. M. Bakker-woudenberg - One of the best experts on this subject based on the ideXlab platform.
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Involvement of T cells in enhanced resistance to Klebsiella pneumoniae septicemia in mice treated with liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamine or gamma interferon.
Infection and immunity, 1998Co-Authors: Timo L.m. Ten Hagen, W. Van Vianen, Huub F. J. Savelkoul, Hubertine Heremans, W. A. Buurman, Irma A. J. M. Bakker-woudenbergAbstract:We have previously shown that prophylactic administration of the liposome-encapsulated immunomodulating agents Muramyl Tripeptide phosphatidylethanolamine (MTPPE) and gamma interferon (IFN-γ) results in strongly increased survival of mice from a normally lethal septicemia with Klebsiella pneumoniae. It was anticipated that the treatment acts on macrophages and nonspecifically augments host resistance to various infections. In the present study, we provide evidence for a key role for T cells in host defense potentiation by the liposomal immunomodulators toward K. pneumoniae septicemia. It is shown that both CD4 and CD8 cells are important in immunomodulation, most likely due to production of IFN-γ. Depletion of circulating IFN-γ resulted in strong reduction of the antimicrobial host defense activation. Administration of interleukin-10 resulted in decreased antimicrobial host defense activation by liposomal immunomodulators. Moreover, administration of liposomal immunomodulators was shown to induce predominantly T-helper type 1 (Th1) cell populations in the spleen. These findings indicate that immunomodulation with liposomal MTPPE and IFN-γ favors Th1 and NK cell activation.
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Modulation of Nonspecific Antimicrobial Resistance of Mice to Klebsiella Pneumoniae Septicemia by Liposome-Encapsulated Muramyl Tripeptide Phosphatidylethanolamine and Interferon-ã Alone or Combined
The Journal of infectious diseases, 1995Co-Authors: Timo L.m. Ten Hagen, W. Van Vianen, Irma A. J. M. Bakker-woudenbergAbstract:Activation of the host defense system in a nonspecific way might provide tools to support failing antibiotic treatment in certain infectious diseases. The antimicrobial effect was investigated of liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamine (MTPPE) and interferon (IFN)-gamma and liposome-coencapsulated MTPPE and IFN-gamma on Klebsiella pneumoniae septicemia in mice. Prophylactic treatment of mice with five doses of liposomal MTPPE or IFN-gamma increased survival from 0 to 65%. Administration of MTPPE and IFN-gamma coencapsulated in liposome resulted in 100% survival. In vitro, peritoneal macrophages by themselves were stimulated by these agents but were unable to kill K. pneumoniae. However, production of both oxygen and nitrogen intermediates increased when immunomodulators were added to macrophages. These results indicate that effective prophylactic treatment of septicemia due to K. pneumoniae with coencapsulated MTPPE and IFN-gamma is not solely due to activation of the resident macrophages.
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Treatment of Klebsiella pneumoniae septicemia in normal and leukopenic mice by liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamide.
Antimicrobial agents and chemotherapy, 1994Co-Authors: P. M. B. Melissen, W. Van Vianen, Irma A. J. M. Bakker-woudenbergAbstract:The effect of free Muramyl Tripeptide phosphatidylethanolamide (MTPPE) and liposome-encapsulated MTPPE (LE-MTPPE) on Klebsiella pneumoniae septicemia resulting from intraperitoneal bacterial inoculation was investigated in mice. When administering a single prophylactic dose at 24 h before bacterial inoculation, the percentage survival was 55% (MTPPE) or 40% (LE-MTPPE), whereas untreated control mice died. Only repeated prophylactic treatment with LE-MTPPE could further increase survival up to 85%.
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Free versus liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamide (MTPPE) and interferon-y (IFN-y) in experimental infection with Listeria Monocytogenes
Biotherapy, 1993Co-Authors: P. M. B. Melissen, W. Vianen, O. Bidjai, M. Marion, Irma A. J. M. Bakker-woudenbergAbstract:The effect of free and liposome-encapsulated Muramyl Tripeptide phosphatidylethanolamide (MTPPE) and interferon- y (IFN- y ) on the resistance against Listeria monocytogenes infection in mice was investigated. It was shown that administration of MTPPE or IFN- y at 24 h before bacterial inoculation led to increased resistance against L. monocytogenes infection in terms of a decrease in bacterial numbers in liver and spleen. Encapsulation of MTPPE and IFN- y in liposomes increased their efficacy 33- or 66-fold, respectively. In addition, liposomal encapsulation led to a more rapid decrease in bacterial numbers. The immunomodulator to lipid ratio appeared to be very important in the antibacterial effect of LE-MTPPE and LE-IFN- y . When nontherapeutic doses of liposome-encapsulated MTPPE or IFN- y were administered in a larger amount of lipid (so at higher lipid: immunomodulator ratio), these doses became effective. Exposure of macrophages in monolayer infected with L. monocytogenes in vitro to MTPPE had no effect, whereas exposure to IFN- y only led to growth inhibition of the intracellular bacteria. However, incubation of macrophages with a combination of MTPPE and IFN- y resulted in killing of the intracellular bacteria. Exposure of macrophages in vivo to both immunomodulators in combination can be effected by using liposomes as carriers. It was observed that administration of MTPPE and IFN- y co-encapsulated in liposomes resulted in a synergistic enhanced antibacterial resistance against L. monocytogenes . Both reactive oxygen and nitrogen intermediates seemed to play a role in the killing of L. monocytogenes by macrophages activated with a combination of MTPPE and IFN- y .
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Treatment of Klebsiella pneumoniae Septicemia in Normal and Leukopenic Mice by Liposome-Encapsulated Muramyl
1993Co-Authors: P. M. B. Melissen, W. Van Vianen, Irma A. J. M. Bakker-woudenberg, Tripeptide PhosphatidylethanolamideAbstract:phosphatidylethanolamide. liposome-encapsulated Muramyl Tripeptide bysepticemia in normal and leukopenic mice Treatment of Klebsiella pneumonia
Alexander Jaho Chou - One of the best experts on this subject based on the ideXlab platform.
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Muramyl Tripeptide phosphatidyl ethanolamine encapsulated in liposomes l mtp pe in the treatment of osteosarcoma
Advances in Experimental Medicine and Biology, 2014Co-Authors: Paul A Meyers, Alexander Jaho ChouAbstract:Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified Muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in Muramyl Tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal Muramyl Tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.
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addition of Muramyl Tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma a report from the children s oncology group
Cancer, 2009Co-Authors: Alexander Jaho Chou, Mark Krailo, John H Healey, Donna L Betcher, Eugenie S Kleinerman, Ernest U Conrad, Michael L Nieder, Michael A Weiner, Zhengjia Chen, Robert J WellsAbstract:BACKGROUND: The addition of liposomal Muramyl Tripeptide phosphatidylethanolamine (MTP-PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP-PE to chemotherapy for patients with metastatic OS. METHODS: Intergroup-0133 was a prospective randomized phase 3 trial for the treatment of newly diagnosed patients with OS. The authors compared 3-drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same 3 drugs with the addition of ifosfamide (Regimen B). The addition of liposomal MTP-PE to chemotherapy was evaluated. RESULTS: Five-year event-free survival (EFS) for patients who received liposomal MTP-PE (n = 46) was 42% versus 26% for those who did not (n = 45) (relative risk for liposomal MTP-PE, 0.72; P = .23; 95% confidence interval [CI], 0.42-1.2). The 5-year overall survival for patients who received MTP-PE versus no MTP-PE was 53% and 40%, respectively (relative risk for liposomal MTP-PE, 0.72; P = 0.27; 95% CI, 0.40-1.3). The comparison of Regimen A with Regimen B did not suggest a difference for EFS (35% vs 34%, respectively; relative risk for Regimen B, 1.07; P = .79; 95% CI, 0.62-1.8) or overall survival (52% vs 43%, respectively; relative risk for Regimen B, 1.1, P = .75; 95% CI, 0.61-2.0). CONCLUSIONS: When the metastatic cohort was considered in isolation, the addition of liposomal MTP-PE to chemotherapy did not achieve a statistically significant improvement in outcome. However, the pattern of outcome is similar to the pattern in nonmetastatic patients. Cancer 2009. © 2009 American Cancer Society.
