Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer.
Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer.
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DOI：
10.1007/s00262-012-1324-3
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发表时间：
2013-02
影响因子：
5.8
通讯作者：
Hollingsworth, Michael A.
中科院分区：
文献类型：
--
作者：
Bunt, Stephanie K.;Mohr, Ashley M.;Bailey, Jennifer M.;Grandgenett, Paul M.;Hollingsworth, Michael A.
胰腺导管腺癌(PDA)是导致癌症死亡的主要原因，5年生存率低达2-5%。吉西他滨单一疗法的成功有限，这突显出需要额外的疗法来提高当前疗法的疗效。我们评估了吉西他滨和罗格列酮的组合，罗格列酮是FDA批准的治疗II型糖尿病的药物，在免疫活性可移植的小鼠胰腺癌模型中。用吡格列酮、罗格列酮、吉西他滨或它们的组合治疗免疫功能正常的小鼠皮下或原位胰腺肿瘤，评估肿瘤进展、存活和转移。我们描述了大剂量罗格列酮和吉西他滨治疗对免疫抑制介质的影响，包括MDSC和T调节细胞，以及对外周和肿瘤内T细胞群的调节。与单独使用吉西他滨相比，罗格列酮和吉西他滨的联合使用显著减少了肿瘤的进展和转移，促进了细胞凋亡，并显著延长了总生存期。罗格列酮通过限制早期MDSC积聚和肿瘤内T调节细胞改变肿瘤相关免疫抑制介质。罗格列酮和吉米可联合治疗通过增强循环中的CD8+T细胞和肿瘤内的D4+和CD8+T细胞来调节T细胞群，同时限制T调节细胞。结果表明，罗格列酮联合吉西他滨可降低免疫活性动物的免疫抑制机制，为罗格列酮和吉西他滨联合治疗胰腺癌提供了临床前数据。
Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer mortality with a dismal 2–5% 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival and metastases were evaluated in immunocompetent mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine or combinations of these. We characterized the impact of high dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitable modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral D4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer.
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影响因子：
3.6
作者：
Grommes, Christian;Landreth, Gary E.;Heneka, Michael T.
通讯作者：
Heneka, Michael T.
影响因子：
6.4
作者：
Necela, Brian M.;Su, Weidong;Thompson, E. Aubrey
通讯作者：
Thompson, E. Aubrey
影响因子：
24.5
作者：
Galli, A;Ceni, E;Casini, A
通讯作者：
Casini, A
影响因子：
3
作者：
Ferrari, V;Valcamonico, F;Marini, G
通讯作者：
Marini, G
DOI：
10.1016/j.bbrc.2004.08.151
发表时间：
2004-10-22
影响因子：
3.1
作者：
Hirakata, M;Tozawa, R;Sugiyama, Y
通讯作者：
Sugiyama, Y