Assessment of overcoming effect for multidrug resistance with photodynamic therapy for esophageal cancer and development of newly combination treatment with chemotherapy and photodynamic therapy

• Project/Area Number: 20K17694
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: University of Miyazaki
• Principal Investigator: Kai Kengo 宮崎大学, 医学部, 助教 (90851585)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 光線力学療法 / 薬剤耐性軽減効果 / talaporfin sodium / 未分化型胃癌細胞株 / 腹膜播種 / 薬剤耐性トランスポーター / 胃癌細胞株 / photodynamimc priming / 薬剤耐性 / 化学療法 / 併用療法 / 食道癌

Outline of Research at the Start

PDTによる化学療法薬剤に対する耐性軽減効果に着目し、シスプラチン耐性食道癌細胞株を用いた培養細胞及びマウスがん異種移植モデル、臨床研究として化学放射線療法後局所再発病変に対するPDT療法後の食道癌生検組織を用いて、耐性軽減メカニズムの解明を目的とする本研究の立案に至った。PDT後に遺残した非治癒腫瘍細胞における化学療法耐性軽減を証明することで、難治性癌に対してPDT療法後に化学療法をre-challengeする選択肢や、低濃度PS、低照射レーザーの副作用を軽減したPDTと化学療法の併用療法など、新たな癌制御の開発を目指す。

Outline of Final Research Achievements

In this study, we conducted immunohistochemistry using clinical samples of esophageal cancer and cell culture to verify the effect of low-intensity photodynamic therapy (PDT) in reducing chemoresistance. With clinical samples, we quantified and compared the expression of breast cancer resistance protein (BCRP) before and after treatment using Image-J software, evaluating the staining intensity of BCRP in the nucleus and cytoplasm of tumor cells. However, we did not observe any significant differences in BCRP expression between pre- and post-treatment for both the nucleus (p=0.459) and cytoplasm (p=0.313). On the other hand, we confirmed that combining low-intensity PDT with the cytotoxic anticancer agent laserfirin for undifferentiated gastric cancer cell lines could improve drug sensitivity to the level of differentiated gastric cancer cell lines.

Academic Significance and Societal Importance of the Research Achievements

PDTの新しいメカニズムである低強度TS-PDT付加による薬剤感受性改善効果（photodynamic priming effect）を未分化型胃癌細胞株を用いたin vitro実験で明らかにした。次なるステップとして、TS-PDP後の胃癌細胞株を用いた治療耐性因子（薬剤排泄トランスポーター、癌幹細胞マーカーなど）の挙動を免疫組織化学やPCR法で評価し、腹膜播種モデルマウスを用いたPDP効果の検証を行うことで、従来の癌治療では効果が得られなかった胃癌腹膜播種などの難治性癌に対する新たな治療法を開発したい。

Research Products

• [Journal Article] A Preliminary Pathological Evaluation of Extracellular Volume Fraction with Contrast-enhanced Computed Tomography as a Novel Quantitative Parameter of Pancreatic Fibrosis (2023)
  • Author(s): Kai Kengo、Hiyoshi Masahide、Imamura Naoya、Hamada Takeomi、Yano Koichi、Sato Yuichiro、Sakae Takehumi、Komi Masanori、Nakamura Takashi、Choijookhuu Narantsog、Hishikawa Yoshitaka、Nanashima Atsushi
  • Journal Title: Internal Medicine Volume: 62 Issue: 8 Pages: 1107-1115
  • DOI: 10.2169/internalmedicine.0410-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2023-04-15
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular Volume Fraction Calculated Using Contrast-Enhanced Computed Tomography as a Biomarker of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome: A Preliminary Histopathological Analysis (2023)
  • Author(s): Kengo Kai, Takeomi Hamada, Yuichiro Sato, Masahide Hiyoshi, Naoya Imamura, Koichi Yano, Takuto Ikeda, Akiko Ichihara, Shogo Ogata, Narantsog Choijookhuu, Yoshitaka Hishikawa, Ayumu Hosokawa, Atsushi Nanashima
  • Journal Title: Journal of Oncology Volume: 2023 Pages: 1440257-1440257
  • DOI: 10.1155/2023/1440257
  • Peer Reviewed / Open Access
• [Journal Article] An alternative option of the retroperitoneal laparoscopic approach for limited hepatectomy for recurrent hepatocellular carcinoma at the transected edge after previous hepatectomy (2023)
  • Author(s): Hamada Takeomi、Yano Koichi、Kitamura Eiji、Hiyoshi Masahide、Imamura Naoya、Kai Kengo、Tahira Kosei、Kawano Fumiya、Ohta Yusuke、Nanashima Atsushi
  • Journal Title: Asian Journal of Endoscopic Surgery Volume: - Issue: 3 Pages: 567-570
  • DOI: 10.1111/ases.13185
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal role of High-Mobility Group Box 2 in ovarian folliculogenesis and fertility (2022)
  • Author(s): Shinichiro Shirouzu, Naohiro Sugita, Narantsog Choijookhuu, Yu Yamaguma, Kanako Takeguchi, Takumi Ishizuka, Mio Tanaka, Fidya, Kengo Kai, Etsuo Chosa, Yoshihiro Yamashita, Chihiro Koshimoto, Yoshitaka Hishikawa
  • Journal Title: Journal of Ovarian Research Volume: 15 Issue: 1 Pages: 133-133
  • DOI: 10.1186/s13048-022-01071-4
  • Peer Reviewed / Open Access
• [Journal Article] Using indocyanine green fluorescence in laparoscopic surgery to identify and preserve rare branching of the right hepatic artery in pediatric congenital biliary dilatation (2022)
  • Author(s): Masuya Ryuta、Matsukubo Makoto、Nakame Kazuhiko、Kai Kengo、Hamada Takeomi、Yano Koichi、Imamura Naoya、Hiyoshi Masahide、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 52 Issue: 10 Pages: 1510-1513
  • DOI: 10.1007/s00595-022-02516-5
  • Peer Reviewed / Open Access
• [Presentation] Charlson Comorbidity IndexがCRT後遺残再発食道癌に対するPDTの治療効果に与える影響 (2022)
  • Author(s): 甲斐 健吾, 中島 孝二, 河上 洋, 武野 慎介, 菱川 善隆, 池ノ上 実, 濱田 剛臣, 今村 直哉, 柴田 智隆, 乗冨 智明, 佐々木 文郷, 中 村 義孝, 七島 篤志
  • Organizer: 第32回日本光線力学学会学術講演会
• [Presentation] 造影CTデータにより算出する細胞外容量分画を用いたオキサリプラチン誘発性類洞障害の診断能についての検討 (2022)
  • Author(s): 甲斐 健吾, 佐藤 勇一郎, 細川 歩, 旭吉 雅秀, 今村 直哉, 矢野 公一, 濱田 剛臣, 市原 明子, 緒方 祥吾, Narantsog Choijookhuu, 菱 川 善隆, 七島 篤志
  • Organizer: 九州がんプロ養成プラン教育研究成果発表会
• [Presentation] マウス卵巣におけるHMGB2の卵胞形成への関与 (2022)
  • Author(s): 山隈 優, Narantsog Choijookhuu, 甲斐 健吾, Fidya, 白水 慎一郎, 石塚 匠, 菱川 善隆
  • Organizer: 第128回日本解剖学会総会・全国学術集会