3103 - Combined Oxygen Ion Beam Irradiation and Gemcitabine Treatment of Pancreatic Cancer - An In Vitro Investigation
Presenter(s)
L. Mai1, J. M. M. Schneeweiss1, M. Allers1, S. Brons2, M. Liu1, R. L. Perez1, J. Debus1,2, and P. E. Huber1,2; 1Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, 2Radiation Oncology & Heidelberg Ion Therapy (HIT), University Hospital Heidelberg, Heidelberg, Germany
Purpose/Objective(s): Pancreatic cancer (PCA) is a devastating disease characterized by poor prognosis and high resistance to chemotherapy and radiotherapy (RT), partly due to the hypoxic tumor microenvironment. Heavy ions, including carbon beam radiotherapy (¹²C-RT) are a promising RT modality for PCA. As ¹6O-RT is considered particularly effective in treating hypoxic tumors, this study systematically investigates oxygen beam radiotherapy (¹6O-RT) as a treatment option for PCA. Specifically, we examine the effects of ¹6O-RT and its combination with gemcitabine as a radio-chemotherapy approach, comparing its efficacy to ¹²C-RT and photon radiotherapy (Ph-RT).
Materials/Methods: Human PCA cell lines (Panc-1, BxPC-3) were treated with different doses of gemcitabine (1 µM to 40 µM, 0 µM as control) and irradiated with ¹6O-RT or ¹²C-RT at the heavy ion therapy center, or with Ph-RT (X-rays). The dose range was 0 Gy to 9 Gy for Ph-RT and 0 Gy to 3 Gy for ¹6O-RT and ¹²C-RT. Optimal doses for all treatment modalities were determined using colony formation and proliferation assays. A detailed radiobiological characterization of cellular responses to combined treatments included clonogenic survival assays, cell proliferation analysis, apoptosis measurements, DNA damage response dynamics via ?H2AX (flow cytometry), and micronuclei induction quantification (microscopy).
Results: Although ¹6O-RT induced a similar reduction in clonogenic survival and DNA damage response as ¹²C-RT, it exhibited higher a values when survival curves were fitted using the linear-quadratic model (1.11 vs. 0.85 in Panc-1, 1.48 vs. 1.21 in BxPC-3). Both heavy-ion beams demonstrated greater radiobiological effectiveness (RBE) compared to Ph-RT, with RBE values favoring ¹6O-RT over ¹²C-RT in both cell lines: [RBE50(¹²C) = 4.41 vs. RBE50(¹6O) = 5.03 in Panc-1; RBE50(¹²C) = 3.91 vs. RBE50(¹6O) = 4.92 in BxPC-3]. Combined treatment experiments revealed enhanced radiosensitivity and at least additive anti-tumor effects compared to RT alone across all irradiation modalities when combined with gemcitabine, as evidenced by reduced clonogenic survival and increased apoptosis rates.
Conclusion: This study demonstrates that ¹6O-RT exhibits comparable yet slightly enhanced anti-tumor efficacy relative to ¹²C-RT. Both ¹6O-RT and ¹²C-RT showed superior biological effectiveness against PCA cells compared to Ph-RT. When combined with gemcitabine, the distinct radiobiological properties of each irradiation modality remained consistent, with at least additive anti-tumor effects observed in all treatment groups. This study establishes a radiobiological foundation for in vivo investigations of ¹6O-RT as a potential treatment strategy for pancreatic cancer and underscores its potential for inclusion in radio-chemotherapy regimens.