title: The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine.
abstract: 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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, S, Euclid Avenue, St. Louis, MO, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hornick
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Mitchem
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitzer
authors.forename: Peter
authors.initials: P
authors.lastname: Goedegebuure
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: William G
authors.initials: WG
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D017480:Receptors, sigma; C106107:sigma-2 receptor; D003841:Deoxycytidine; D053148:Caspase 3; D000093542:Gemcitabine