The combination of APO2L/TRAIL with protein synthesis inhibitors or tyrosine kinase inhibitors inhibits pancreatic cancer growth in vitro and in vivo

J. Standop MD, F. Nozawa MD, M. Schneider MD, R.E. Brand MD a, X.Z. Ding MD b, A. Ulrich MD, K. Picha c, T.E. Adrian PhD b, and P.M. Pour MD.

UNMC Eppley Institute, and aDepartment of Gastroenterology, University of Nebraska Medical Center, Omaha, NE. bCreighton University, Omaha, NE. cImmunex Corp., Seattle, WA.

Aim: The poor prognosis of pancreatic cancer (PC) and its resistance to conventional therapies call for urgent development of new treatment schemes. Our studies have demonstrated that Apo2L/TRAIL (TNF-related-apoptosis-inducing-ligand, TRAIL) induces apoptosis in six of seven PC cell lines, but has no apoptotic effect on AsPC-1 cells. Consequently, it was of interest to identify compounds that in combination with TRAIL can overcome the resistance of AsPC-1 cells. Methods: In vitro: AsPC-1 cells were treated for 24 hours with either TRAIL, alkylating agents (cyclophosphamide, ifosphamide, mafosphamide), protein synthesis inhibitors (cycloheximide, anisomycin, emetine), NF-kappaB inhibitors (sulfasalazine), and tyrosine kinase inhibitors (genistein) alone, or in combination with TRAIL. In vivo: 1x106 AsPC-1 cells were orthotopically transplanted into athymic nude mice. Ten days later, the mice were treated with cycloheximide (CHX) or genistein (GST) alone or in combination with TRAIL daily for 10 days, after which the tumor size and volume were measured in each group. Results: In vitro, only the combination of TRAIL+protein synthesis inhibitors and TRAIL+GST was effective in inhibiting the growth of AsPC-1 cells. The combination with CHX increased the rate of apoptosis significantly. In vivo, a significant inhibition of tumor growth was found in all mice receiving the combination regimen. Conclusion: The combination of Apo2L/TRAIL with either a protein synthesis inhibitor or a tyrosine kinase inhibitor appears to be a promising regimen for PC therapy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.