The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine
The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine
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DOI：
10.1186/1476-4598-9-298
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发表时间：
2010-11-22
期刊：
影响因子：
37.3
通讯作者：
Hawkins, William G.
中科院分区：
文献类型：
--
作者：
Hornick, John R.;Xu, Jinbin;Hawkins, William G.
背景资料：σ-2受体在增殖的癌细胞中过表达，成为胰腺癌靶向治疗的有吸引力的靶标。结果：胰腺癌组织中sigma-2受体配体与胰腺癌细胞的结合亲和力较高，体外诱导胰腺癌细胞凋亡的能力为SV 119 <SW 43 < SRM。这些化合物与吉西他滨组合进一步增加了细胞凋亡并降低了生存力。我们的体内模型显示，σ-2配体治疗与吉西他滨相同程度地减小肿瘤体积。然而，SW 43与吉西他滨的组合治疗上级其他化合物，并且在治疗期间导致肿瘤体积的稳定，具有最小的毒性。这项研究表明，σ-2配体SW 43在预治疗中具有最大的增加吉西他滨的能力。胰腺癌的临床模型，并为我们提供了将这种化合物用于临床研究的基本原理，胰腺癌
Background: Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. In this study, we investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy.Results: The binding affinity for sigma-2 ligands is high in pancreas cancer, and they induce apoptosis with a rank order of SV119 < SW43 < SRM in vitro. Combining these compounds with gemcitabine further increased apoptosis and decreased viability. Our in vivo model showed that sigma-2 ligand treatment decreased tumor volume to the same extent as gemcitabine. However, SW43 combination treatment with gemcitabine was superior to the other compounds and resulted in stabilization of tumor volume during treatment, with minimal toxicities.Conclusions: This study shows that the sigma-2 ligand SW43 has the greatest capacity to augment gemcitabine in a pre-clinical model of pancreas cancer and has provided us with the rationale to move this compound forward with clinical investigations for patients with pancreatic cancer.