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Xenografts Derived From Patients' Ascites Recapitulate the Gemcitabine Resistance Observed in Pancreatic Cancer Patients

Machinaga, Akihito PhD*; Hori, Yuichi MD, PhD; Shimizu, Kazuya MD, PhD†,‡; Okahara, Kyohei PhD*; Yanagita, Emmy BD§; Miyoshi, Makoto PhD; Itoh, Tomoo MD, PhD§; Sasai, Ken PhD*

doi: 10.1097/MPA.0000000000001438
Original Articles
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Objectives Most patient-derived pancreatic ductal adenocarcinoma (PDAC) xenografts have been established from surgical specimens of patients who have not received chemotherapy. However, xenografts have rarely been established from chemotherapy-resistant, advanced PDACs, because such cases are usually inoperable. The purpose of this study is to establish patient-derived xenografts using PDAC cells refractory to chemotherapy.

Methods Clinical PDAC cells obtained from ascites of patients who had received continuous chemotherapy were implanted into the flanks of immunocompromised mice. Growth and histological features of the xenografts with and without gemcitabine treatment were then analyzed.

Results Ascites-derived PDAC cells were successfully expanded through serial xenograft passage without changes in histological appearance. While treatment with gemcitabine substantially inhibited the growth of all PDAC xenografts tested, the tumor volume gradually increased, and the tumors showed marked regrowth even under continued gemcitabine treatment. These findings are consistent with the actual clinical course of the corresponding patients for each xenograft.

Conclusions Ascites-derived xenograft models represent a valuable experimental system for testing the efficacy of currently available therapeutic compounds on chemotherapy-resistant PDAC cells and for elucidation of the mechanisms underlying chemotherapy resistance.

From the *KAN Research Institute, Inc

Department of Biophysics, Kobe University Graduate School of Health Sciences

Department of Internal Medicine, National Hospital Organization Kobe Medical Center

§Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.

Received for publication December 11, 2018; accepted September 22, 2019.

Address correspondence to: Ken Sasai, PhD, KAN Research Institute Inc, 6-8-2 Minatojima-Minanimachi, Chuo-ku, Kobe 650-0047, Japan (e-mail: k-sasai@kan.eisai.co.jp); or Yuichi Hori, MD, PhD, Department of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe 654-0142, Japan (e-mail: horiy@people.kobe-u.ac.jp).

E.Y. is now with the Division of Clinical Cancer Genomics, School of Medicine, Keio University, Tokyo, Japan.

This study was supported in part by Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.H. (18K08705) and K. Shimizu (17K10697).

A.M., K.O., and K. Sasai are employees of KAN Research Institute, Inc. KAN Research Institute is a subsidiary of Eisai Inc, which is the research funder of this study. The other authors declare no conflict of interest.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.