Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma.
Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma.
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DOI：
10.1186/1479-5876-7-24
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发表时间：
2009-03-26
影响因子：
7.4
通讯作者：
Hawkins WG
中科院分区：
文献类型：
--
作者：
Kashiwagi H;McDunn JE;Simon PO Jr;Goedegebuure PS;Vangveravong S;Chang K;Hotchkiss RS;Mach RH;Hawkins WG
我们以前报道过sigma-2受体在胰腺癌中高度表达。此外，我们已经证明了sigma-2受体特异性配体以剂量依赖性的方式诱导细胞凋亡。在这里，我们研究了sigma-2受体配体是否增强了常规化疗，如吉西他滨和紫杉醇。本研究采用小鼠（Panc-02）和人（CFPAC-1、Panc-1、AsPC-1）胰腺癌细胞系。TUNEL和Caspase-3染色后，采用流式细胞术或免疫组化检测细胞凋亡。在异体胰腺癌动物模型中，对sigma-2配体SV119与常规化疗吉西他滨和紫杉醇联合治疗进行了评估。SV119、吉西他滨和紫杉醇在所有胰腺癌细胞系中以剂量依赖的方式诱导细胞凋亡。联合用药可增加细胞凋亡。小鼠用SV119 （1 mg/d）联合紫杉醇（300 μg/d）治疗已建立肿瘤的小鼠，持续7天。联合治疗有生存获益（p = 0.0002）。每隔一天使用SV119 （1mg /天）联合每周使用吉西他滨（1.5 mg/周）治疗2周，也显示出生存获益（p = 0.046）。动物耐受联合治疗，血清生化数据和尸检均未发现明显毒性。SV119增强了紫杉醇和吉西他滨的杀肿瘤活性，无主要副作用。这些结果突出了sigma-2配体作为胰腺癌辅助治疗的潜在效用。
We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. Furthermore, we have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. Here, we examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel. Mouse (Panc-02) and human (CFPAC-1, Panc-1, AsPC-1) pancreas cancer cell lines were used in this study. Apoptosis was determined by FACS or immunohistochemical analysis after TUNEL and Caspase-3 staining. Combination therapy with the sigma-2 ligand SV119 and the conventional chemotherapies gemcitabine and paclitaxel was evaluated in an allogenic animal model of pancreas cancer. SV119, gemcitabine, and paclitaxel induced apoptosis in a dose-dependent fashion in all pancreas cancer cell lines tested. Combinations demonstrated increases in apoptosis. Mice were treated with SV119 (1 mg/day) which was administered in combination with paclitaxel (300 μg/day) over 7 days to mice with established tumors. A survival benefit was observed with combination therapy (p = 0.0002). Every other day treatment of SV119 (1 mg/day) in combination with weekly treatment of gemcitabine (1.5 mg/week) for 2 weeks also showed a survival benefit (p = 0.046). Animals tolerated the combination therapy and no gross toxicity was noted in serum biochemistry data or on necropsy. SV119 augments tumoricidal activity of paclitaxel and gemcitabine without major side effects. These results highlight the potential utility of the sigma-2 ligand as an adjuvant treatment in pancreas cancer.
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影响因子：
11.2
作者：
Ostenfeld, MS;Fehrenbacher, N;Jäättelä, M
通讯作者：
Jäättelä, M
影响因子：
2.9
作者：
Sierzega, Marek;Popiela, Tadeusz;Nowak, Krystyna
通讯作者：
Nowak, Krystyna
DOI：
10.1016/j.jsgi.2003.11.003
发表时间：
2004-05-01
期刊：
JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION
影响因子：
--
作者：
Flick, MB;O'Malley, D;Mor, G
通讯作者：
Mor, G
影响因子：
3.1
作者：
Choi, SR;Yang, B;Kung, HF
通讯作者：
Kung, HF
DOI：
10.1016/j.jamcollsurg.2003.12.005
发表时间：
2004-04-01
影响因子：
5.2
作者：
Fahy, BN;Schlieman, MG;Bold, RJ
通讯作者：
Bold, RJ