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Conference Paper: Targeting polyamines as potential adjuvant therapy in malignant pleural mesothelioma xenograft models
Title | Targeting polyamines as potential adjuvant therapy in malignant pleural mesothelioma xenograft models |
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Authors | |
Keywords | Difluoromethylornithine Mesothelioma |
Issue Date | 2018 |
Publisher | Elsevier Inc. The Journal's web site is located at http://www.jto.org |
Citation | IASLC 19th World Conference on Lung Cancer, Toronto, Canada, 23-26 September 2018. In Journal of Thoracic Oncology, 2018, v. 13 n. 10, Suppl., p. S749-S750 How to Cite? |
Abstract | Background: Inhaling asbestos fibers is one of the commonest of malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM is still rising due to a long lag time in malignant transformation. In 2004, the US Food and Drug Administration approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. At the same time, development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. Ornithine decarboxylase (ODC) is highly expressed in 211H and H226 MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamine production and enhances tumor growth. -difluoromethylornithine (DFMO) is a specific ODC inhibitor. Recent preclinical studies have demonstrated the adjuvant effect of DFMO in colon cancers using xenograft model. However, adjuvant effect of DFMO in MPM has not yet been studied. This study aims to disclose the adjuvant effect of DFMO in MPM xenograft models. The findings from this study will provide scientific foundation for future design of clinical trials of DFMO for adjuvant therapy in early disease for advanced MPM. Methods: Nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells (211H (biphasic) or H226 (epithelioid)). Mice with tumor size >600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentrations, NFB translocation and apoptosis were investigated by Dot plot, Western blot, ELISA, immunofluorescence staining and TUNEL assay respectively. Results: DFMO suppressed tumor growth in both xenografts. DFMO increased median survival from 49.5 days in control arm to 65 days in treatment arm in mice with 211H xenografts (p = 0.08), while from 44 days to 120 days in those with H226 xenografts (p = 0.0002). In H226 xenograft model, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, nuclear translocation of NFkB, elevation of serum IL-6 and activation of apoptosis were observed in both xenografts. In addition, increase in nitrocysteine level, decrease in serum keratinocyte chemoattractant (KC), increase in serum TNF alpha, elevation of DNA lesion and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in this xenograft. Conclusion: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma. Acknowledgment: This research was supported by Hong Kong Pneumoconiosis Compensation Fund Board, HKSAR. |
Description | Poster Sessions - no. P2.06-19 |
Persistent Identifier | http://hdl.handle.net/10722/272706 |
ISSN | 2023 Impact Factor: 21.0 2023 SCImago Journal Rankings: 7.879 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Lam, SK | - |
dc.contributor.author | Yan, S | - |
dc.contributor.author | Xu, S | - |
dc.contributor.author | Ho, JCM | - |
dc.date.accessioned | 2019-08-06T09:15:00Z | - |
dc.date.available | 2019-08-06T09:15:00Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | IASLC 19th World Conference on Lung Cancer, Toronto, Canada, 23-26 September 2018. In Journal of Thoracic Oncology, 2018, v. 13 n. 10, Suppl., p. S749-S750 | - |
dc.identifier.issn | 1556-0864 | - |
dc.identifier.uri | http://hdl.handle.net/10722/272706 | - |
dc.description | Poster Sessions - no. P2.06-19 | - |
dc.description.abstract | Background: Inhaling asbestos fibers is one of the commonest of malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM is still rising due to a long lag time in malignant transformation. In 2004, the US Food and Drug Administration approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. At the same time, development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. Ornithine decarboxylase (ODC) is highly expressed in 211H and H226 MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamine production and enhances tumor growth. -difluoromethylornithine (DFMO) is a specific ODC inhibitor. Recent preclinical studies have demonstrated the adjuvant effect of DFMO in colon cancers using xenograft model. However, adjuvant effect of DFMO in MPM has not yet been studied. This study aims to disclose the adjuvant effect of DFMO in MPM xenograft models. The findings from this study will provide scientific foundation for future design of clinical trials of DFMO for adjuvant therapy in early disease for advanced MPM. Methods: Nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells (211H (biphasic) or H226 (epithelioid)). Mice with tumor size >600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentrations, NFB translocation and apoptosis were investigated by Dot plot, Western blot, ELISA, immunofluorescence staining and TUNEL assay respectively. Results: DFMO suppressed tumor growth in both xenografts. DFMO increased median survival from 49.5 days in control arm to 65 days in treatment arm in mice with 211H xenografts (p = 0.08), while from 44 days to 120 days in those with H226 xenografts (p = 0.0002). In H226 xenograft model, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, nuclear translocation of NFkB, elevation of serum IL-6 and activation of apoptosis were observed in both xenografts. In addition, increase in nitrocysteine level, decrease in serum keratinocyte chemoattractant (KC), increase in serum TNF alpha, elevation of DNA lesion and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in this xenograft. Conclusion: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma. Acknowledgment: This research was supported by Hong Kong Pneumoconiosis Compensation Fund Board, HKSAR. | - |
dc.language | eng | - |
dc.publisher | Elsevier Inc. The Journal's web site is located at http://www.jto.org | - |
dc.relation.ispartof | Journal of Thoracic Oncology | - |
dc.relation.ispartof | IASLC 19th World Conference on Lung Cancer | - |
dc.subject | Difluoromethylornithine | - |
dc.subject | Mesothelioma | - |
dc.title | Targeting polyamines as potential adjuvant therapy in malignant pleural mesothelioma xenograft models | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Lam, SK: sklam77@hku.hk | - |
dc.identifier.email | Yan, S: ssyan@hku.hk | - |
dc.identifier.email | Ho, JCM: jhocm@hku.hk | - |
dc.identifier.authority | Ho, JCM=rp00258 | - |
dc.identifier.doi | 10.1016/j.jtho.2018.08.1274 | - |
dc.identifier.hkuros | 299635 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 10, Suppl. | - |
dc.identifier.spage | S749 | - |
dc.identifier.epage | S750 | - |
dc.identifier.isi | WOS:000454014502424 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 1556-0864 | - |