Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer.
Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer.
复制标题
二甲氨基小白菊内酯和舒林酸联合吉西他滨在胰腺癌基因工程小鼠模型中的疗效。
DOI：
10.1097/mpa.0b013e318254f455
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发表时间：
2013
期刊：
影响因子：
2.9
通讯作者：
Schmidt,ChristianMax
中科院分区：
文献类型：
--
作者：
Yip-Schneider,MicheleT;Wu,Huangbing;Hruban,RalphH;Lowy,AndrewM;Crooks,PeterA;Schmidt,ChristianMax
目的胰腺癌仍然是最致命的疾病之一，手术和治疗选择有限。两个感兴趣的靶点包括转录因子核因子-κB和环氧合酶-2，它们分别在人胰腺癌中结构性激活和过度表达。我们先前已经证明，生物可利用的核因子-κB抑制剂二甲氨基苯内酯以及环氧合酶抑制剂舒林酸和塞来昔布具有潜在的化疗疗效。本研究评估了DMAPT和舒林酸在LSL-Kras G12D；PDX-1-CRE基因工程小鼠模型中的干预效果。吉西他滨是一种传统的化疗药物，毒性相对较低，因此也探索了与小剂量吉西他滨的联合治疗。方法7月龄LSL-Kras G12D；PDX-1-CRE小鼠随机分为安慰剂、DMAPT(40 mg/kg/d)、舒林酸(20 mg/kg/d)、吉西他滨(50 mg/kg，每周2次)和联合治疗组。结果与安慰剂相比，DMAPT/舒林酸、DMAPT/吉西他滨、舒林酸/吉西他滨、DMAPT/舒林酸/吉西他滨联合用药组小鼠的正常胰管百分率明显增加。结论DMAPT和舒林酸联合吉西他滨可延缓或阻止LSL-Kras G12D；PDX-1-CRE小鼠胰腺癌模型胰腺癌前病变的进展。
ObjectivesPancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras G12D; Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored.MethodsLSL-Kras G12D; Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed.ResultsThe percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine.ConclusionsIntervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras G12D; Pdx-1-Cre mouse model of pancreatic cancer.