Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma.
BACKGROUND
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.


METHODS
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.


RESULTS
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 microg/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.


CONCLUSIONS
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.
Kashiwagi
Hiroyuki
H
Department of Surgery, Washington University School of Medicine, 660 S, Euclid Avenue, Campus Box 8109, St, Louis, MO 63110, USA. hawkinsw@wustl.edu
McDunn
Jonathan E
JE
Simon
Peter O
PO
Goedegebuure
Peter S
PS
Vangveravong
Suwanna
S
Chang
Katherine
K
Hotchkiss
Richard S
RS
Mach
Robert H
RH
Hawkins
William G
WG