Electrochemotherapy with Irreversible Electroporation and FOLFIRINOX Improves Survival in Murine Models of Pancreatic Ad
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ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH
Electrochemotherapy with Irreversible Electroporation and FOLFIRINOX Improves Survival in Murine Models of Pancreatic Adenocarcinoma Neal Bhutiani, MD, PhD1, Yan Li, MD, PhD1, Qianqian Zheng, PhD2, Harshul Pandit, PhD1, Xiaoju Shi, MD, PhD3, Yujia Chen, MD4, Youxi Yu, MD3, Zachary R. Pulliam, BS1, Min Tan, MD, PhD1, and Robert C. G. Martin II, MD, PhD, FACS1 1
Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY; Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang, China; 3Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China; 4Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, China
2
ABSTRACT Background. Previously published work has demonstrated that combining gemcitabine with irreversible electroporation (IRE) results in increased drug delivery to pancreatic adenocarcinoma cells in vivo. This study assessed the efficacy of IRE ? gemcitabine and IRE ? FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), the impact of the superior regimen on survival, and the safety of electrochemotherapy in human subjects. Methods. Histologic analysis was performed after in vitro and in vivo treatment of S2013 and Panc-1 pancreatic cancer cells and S2013 orthotopic tumors, respectively, and levels of apoptotic machinery and cell cycle proteins were evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot. Results. Electrochemotherapy (ECT) with IRE and FOLFIRINOX resulted in increased tumor cells apoptosis compared with gemcitabine, gemcitabine ? IRE, and FOLFIRINOX alone, and significantly improved overall survival when compared with mice treated with IRE or FOLFIRINOX. Increased tumor cell apoptosis, caspase-3 mRNA, active caspase-3 protein, and decreased cell proliferation were noted at the time of death or euthanasia in
Ó Society of Surgical Oncology 2020 First Received: 27 September 2019 Accepted: 5 May 2020 R. C. G. Martin II, MD, PhD, FACS e-mail: [email protected]
the ECT group compared with folinic acid alone. In five patients, ECT with either FOLFIRINOX or gemcitabine was well-tolerated and resulted in no dose-limiting toxicities. Conclusions. ECT thus results in synergistic antitumor activity compared with either treatment modality used alone, resulting in increased tumor cell apoptosis as well as decreased tumor cell proliferation and improved overall survival. Pilot data suggest that ECT represents a promising modality for the treatment of patients with locally advanced pancreatic cancer. Trial Registration. The human subject portion of this work was conducted as part of an investigator-initiated clinical trial at the University of Louisville (NCT03484299).
Pancreatic adenocarcinoma represents a particularly lethal malignancy, especially among patients with advanced disease.1 Even in the era of multiage
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