Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

<p>Abstract</p> <p>Background</p> <p>The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo-...

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Main Authors: Felley-Bosco Emanuela, Kurtz Stefanie, Hopkins-Donaldson Sally, Marti Thomas M, Belyanskaya Larisa L, Stahel Rolf A
Format: Article
Language:English
Published: BMC 2007-10-01
Series:Molecular Cancer
Online Access:http://www.molecular-cancer.com/content/6/1/66
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author Felley-Bosco Emanuela
Kurtz Stefanie
Hopkins-Donaldson Sally
Marti Thomas M
Belyanskaya Larisa L
Stahel Rolf A
author_facet Felley-Bosco Emanuela
Kurtz Stefanie
Hopkins-Donaldson Sally
Marti Thomas M
Belyanskaya Larisa L
Stahel Rolf A
author_sort Felley-Bosco Emanuela
collection DOAJ
description <p>Abstract</p> <p>Background</p> <p>The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.</p> <p>Results</p> <p>We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine.</p> <p>Conclusion</p> <p>Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.</p>
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spelling doaj.art-25f0f18967d34a598e4348d2c2507e232022-12-21T22:00:43ZengBMCMolecular Cancer1476-45982007-10-01616610.1186/1476-4598-6-66Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatinFelley-Bosco EmanuelaKurtz StefanieHopkins-Donaldson SallyMarti Thomas MBelyanskaya Larisa LStahel Rolf A<p>Abstract</p> <p>Background</p> <p>The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.</p> <p>Results</p> <p>We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine.</p> <p>Conclusion</p> <p>Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.</p>http://www.molecular-cancer.com/content/6/1/66
spellingShingle Felley-Bosco Emanuela
Kurtz Stefanie
Hopkins-Donaldson Sally
Marti Thomas M
Belyanskaya Larisa L
Stahel Rolf A
Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
Molecular Cancer
title Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
title_full Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
title_fullStr Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
title_full_unstemmed Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
title_short Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
title_sort human agonistic trail receptor antibodies mapatumumab and lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin
url http://www.molecular-cancer.com/content/6/1/66
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