https://scholars.lib.ntu.edu.tw/handle/123456789/473344
標題: | Potential synergistic anti-tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma | 作者: | DA-LIANG OU Chang C.-J. YUNG-MING JENG Lin Y.-J. ZHONG-ZHE LIN Gandhi A.K. Liao S.-C. Huang Z.-M. CHIUN HSU ANN-LII CHENG |
公開日期: | 2014 | 出版社: | Blackwell Publishing | 卷: | 29 | 期: | 12 | 起(迄)頁: | 2021-2031 | 來源出版物: | Journal of Gastroenterology and Hepatology (Australia) | 摘要: | Background and Aim: The immune modulatory drug lenalidomide has shown promising anti-tumor activity in a clinical trial of patients with advanced hepatocellular carcinoma (HCC). The present study explored whether lenalidomide can enhance the anti-tumor activity of sorafenib, the standard molecular targeted therapy for HCC. Methods: The anti-tumor efficacy of single-agent or combination treatment was measured by change in tumor volume and animal survival using an orthotopic liver cancer model. Distribution of T-cell subpopulations in tumor-infiltrating lymphocytes (TILs) and splenocytes derived from tumor-implanted mice was measured by flow cytometry. Depletion of relevant T-cell subpopulations or cytokines was done by co-administration of relevant antibodies with study drug treatment. Tumor cell apoptosis and tumor angiogenesis were measured by transferase deoxytidyl uridine end labeling assay and immunohistochemical study, respectively. Results: Combination of sorafenib and lenalidomide produced significant synergistic anti-tumor efficacy in terms of tumor growth delay and animal survival. This synergistic effect was associated with a significant increase in interferon-γ expressing CD8+ lymphocytes in TILs and a significantly higher number of granzyme- or perforin-expressing CD8+ T cells, compared with vehicle- or single-agent treatment groups. Combination treatment significantly increased apoptotic tumor cells and vascular normalization in tumor tissue. The synergistic anti-tumor effect was abolished after CD8 depletion. Conclusions: Lenalidomide can enhance the anti-tumor effects of sorafenib in HCC through its immune modulatory effects, and CD8+ TILs play an important role in the anti-tumor synergism. ? 2014 Wiley Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84938888130&doi=10.1111%2fjgh.12708&partnerID=40&md5=fcd5ab0908858803fb2574bd859fcfce https://scholars.lib.ntu.edu.tw/handle/123456789/473344 |
ISSN: | 0815-9319 | DOI: | 10.1111/jgh.12708 | SDG/關鍵字: | alpha actin; collagen type 4; gamma interferon; granzyme; granzyme B; Ki 67 antigen; lenalidomide; perforin; sorafenib; antineoplastic agent; carbanilamide derivative; gamma interferon; immunologic factor; lenalidomide; nicotinamide; sorafenib; thalidomide; animal cell; animal experiment; animal model; animal tissue; antiangiogenic activity; antineoplastic activity; apoptosis; Article; breast cancer cell line; cancer combination chemotherapy; cancer growth; cancer inhibition; cancer size; cancer survival; CD8+ T lymphocyte; cell count; cell disruption; cell stimulation; cell viability; controlled study; cytotoxicity; drug effect; drug efficacy; drug megadose; drug potentiation; drug tolerability; granulocytosis; human; human cell; immunomodulation; in vitro study; in vivo study; leukocytosis; liver cancer cell line; liver carcinogenesis; liver cell carcinoma; low drug dose; lymphocyte count; lymphocytosis; molecularly targeted therapy; monotherapy; mouse; nonhuman; priority journal; protein expression; regulatory T lymphocyte; spleen cell; T cell depletion; T lymphocyte subpopulation; treatment duration; tumor associated leukocyte; tumor microenvironment; upregulation; analogs and derivatives; animal; Carcinoma, Hepatocellular; disease model; drug combination; drug potentiation; immunology; Liver Neoplasms; pathology; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Immunologic Factors; Interferon-gamma; Liver Neoplasms; Mice; Niacinamide; Phenylurea Compounds; T-Lymphocyte Subsets; Thalidomide |
顯示於: | 病理學科所 |
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