Previous studies have shown that Interferon(IFN)-based chemoradiation therapy can improve survival after resection of pancreas cancer. However, its clinical utility to this point has been limited due to the severe toxicity related to its use of systemic IFN. Our aim in this study is to evaluate our group's novel oncolytic adenovirus (OAd) which allows targeting IFN treatment to cancer cells while sparing healthy tissue. We have previously shown the ability of IFN to sensitize cancer cells to chemotherapy as well as demonstrated an increased therapeutic effect of the drug in immunocompetent models. This study was conducted to analyze the combination of 5FU chemotherapy and our OAd in vitro in order to assess the interaction of treatments and determine the optimum combined treatment regimen.
Treatments were analyzed in pancreatic cancer and esophageal adenocarcinoma cell lines S2013 and OE19. Recombinant OAds expressing luciferase rather than IFN were used to isolate the combination of 5FU and the virus. Two viral models were evaluated: our therapeutic virus (Cox2) selectively replicative in Cox2 expressing cancer cells and a nearly identical but universally replicative virus (wild type). Cells were treated with 0, 1 or 10 viral particles per cell and 0, 5, 10, or 20 uM 5FU. Three timing regimens were used: simultaneous administration, 5FU 4 hours before virus, and virus 48 hours before 5FU. Crystal Violet and MTS Assays were used to measure cell death. Viral Copy number to assess viral replication was measured using qPCR.
Cell death analysis showed time dependent killing of each virus, with a 2 day delay for the Cox2 virus. 5FU and each virus produced dose dependent cell death independently. There was a significant additive effect seen in cell death from combining treatments when using 5FU before virus in both S2013 and OE19. Simultaneous treatment showed an additive killing effect with the combination in S2013, but a reduced killing by the combination compared to virus alone in OE19. There was also reduced killing when using virus before 5FU in S2013. Viral copy experiments are in progress.
Our Cox2 OAd shows a killing effect similar to wild type in multiple cancer cell lines. When combined with 5FU treatment the expected addition in overall cell death from the independent treatments varies by timing of administrations as well as by type of cancer cell line. The reduced killing of the combination treatment in the simultaneous and virus before 5FU regimens may suggest an inhibition of the virus by 5FU under certain conditions. This also suggests the possibility of a treatment regimen with optimal therapeutic effect, which appears to be 5FU before virus based on the results collected. Further studies investigating different chemotherapeutic drugs and regimens should be conducted to examine these trends.
Citation Format: Jordan Sell, Amanda Oliviera, Eric Jensen, Masato Yamamoto, Julia Davydova. Interaction of 5FU chemotherapy and oncolytic adenovirus in combined cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3749.