Background: Resistance towards cytotoxic drugs and ionizing radiation (IR) accounts for poor therapy response in pancreatic cancer. The radiosensitizing effects of fluorouracil (FU) are well characterized, however, it is not known whether IR itself exerts sensitizing effects towards cytotoxic chemotherapy. Here, we hypothesize that IR induced upregulation of thymidine phosphorylase (TP) results in a reversal of resistance towards FU.

Methods: An FU resistant variant of the human pancreatic adenocarcinoma cell line AsPC-1 was developed by long term in vitro FU exposure. Proliferation of AsPC-1 and AsPC-1FUres cells was determined by an MTT proliferation assay after previous low dose (0.05 Gy) exposure of IR. To antagonize a possible effect mediated by TP upregulation, anti-TP siRNA was added in the same setting. TP expression in AsPC-1 cells before and after IR was determined by Western blotting.

Results: FU resistant AsPC-1 cells showed a 7.5-fold increase of the IC50 after FU exposure, compared to non-resistant cells. When challenging both cell lines with FU after low dose IR, no significant difference of proliferation was observed in AsPC-1 cells and their FU resistant variant, suggesting a reversal of chemoresistance by IR. This chemosensitizing effect was abrogated when blocking TP by anti-TP siRNA before IR. In cell lysates harvested from AsPC-1 cells, an increase of TP expression was seen after exposure of low dose IR (0.05 Gy) as well as high dose IR (2.0 Gy).

Conclusion: Our results suggest a TP mediated reversal of chemoresistance towards FU that is triggered by low dose IR in vitro. These results have to be confirmed in an in vivo model. In conclusion, induction of TP expression by low dose irradiation may be an interesting concept to overcome chemotherapy resistance in pancreatic cancer.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1330.