Pancreatic cancer has a poor prognosis with an annual mortality rate close to the annual incidence rate. We evaluated whether the expression of measles virus fusogenic
membrane glycoproteins (FMG) H and F will enhance
chemotherapy. Using Chou-Talalay analysis, we showed in vitro in
pancreatic cancer cells that the expression of FMG often synergistically enhances clinically relevant
chemotherapy. Furthermore, cell fusion in combination with
chemotherapy resulted in strongly enhanced
Annexin V binding, an early marker for apoptosis, when compared with single treatment. We showed in an i.p. and s.c. pancreatic xenograft model that the administration of a replication-defective adenoviral vector Ad.H/F encoding
tumor-restricted FMG in combination with
gemcitabine significantly enhanced treatment outcome when compared with treatment with each compound individually. To improve
tumor transduction efficiency, the Ad.H/F vector was also transcomplemented with an oncolytic replication-restricted adenovirus (Ad.COX*MK), resulting in significantly improved treatment efficacy. We assessed treatment efficacy by survival analysis or measuring growth, respectively. In the i.p. model, on day 120, three of eight animals treated with this novel triple
therapy consisting of Ad.H/F,
gemcitabine, and Ad.COX*MK were alive and
tumor free. Treatment with Ad.H/F and Ad.COX*MK resulted in one long-term survivor. In all other treatment groups, there were no long-term survivors. The significantly improved therapeutic outcome of animals receiving the triple
therapy was attributed to multiple factors, including most likely improved FMG expression throughout the
tumor and enhanced sensitivity of the
tumor cells to
gemcitabine by adenoviral gene products but also FMG expression. Qualitatively similar results were obtained in a s.c. pancreatic xenograft model.