Candidate biomarkers for predicting drug response in cancer treatment

• Project/Area Number: 15K08109
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Tokai University
• Principal Investigator: KOBAYASHI Hiroyuki 東海大学, 医学部, 教授 (60195807)
• Co-Investigator(Kenkyū-buntansha): 小見山 智義 東海大学, 医学部, 准教授 (60439685)
• Research Collaborator: Yu Shyr Vanderbilt大学, 癌センター, 教授 ; Hande Kenneth R. Vanderbilt大学, 癌センター, 教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん / 薬剤反応性 / 抗腫瘍薬耐性 / ゲノム変化 / 国際情報交換 米国 / 国際情報交換 米国

Outline of Final Research Achievements

Idarubicin (IDR), which inhibits DNA polymerase, is a key drug to treat leukemia. We investigated the mechanism of resistance using the human leukemia cell line MOLT-3 and its idarubicin-resistant MOLT-3/IDR by mitochondrial DNA and exome nuclear DNA analyses.
In resistant sublines, LIG1 DNA ligase 1 and helicase plurality genes showed amino acid-related changes. Amino acid mutations were also confirmed in polymerase-associated genes. GO enrichment testing was performed and lipid-related genes were selected based on the results. Flow cytometric method was used to determine whether IDR permeability was significantly different in MOLT-3/IDR and MOLT-3. The data showed that an IDR concentration of 0.5 μg resulted in slow permeability in MOLT-3/IDR. The slow IDR permeability seen in MOLT-3/IDR might be due to the effects of the amino acid changes found in polymerase- and lipid-associated genes.
Our findings suggest that multiple mutations in these genes play a role in IDR resistance.

Research Products

• [Int'l Joint Research] Vanderbilt University Medical Center(米国)
• [Journal Article] Lymphatic invasion is a significant indicator of poor patient prognosis in lung squamous cell carcinoma. (2017)
  • Author(s): Masuda R, Kijima H, Nito M, Wada A, Matsuzaki T, Ikoma Y, Nakazato K, Masuda D, Tanaka M, Kobayashi H, Inokuchi S, Iwazaki M.
  • Journal Title: Mol Med Rep. Volume: 15 Issue: 4 Pages: 2067-2073
  • DOI: 10.3892/mmr.2017.6256
  • Peer Reviewed / Open Access
• [Journal Article] Analysis to Estimate Genetic Variations in the Idarubicin-Resistant Derivative MOLT-3. (2016)
  • Author(s): Komiyama T, Ogura J, Hirokawa T, Kamikuchi H, Asai S, Miyachi H, Kobayashi H.
  • Journal Title: Int J Molecular Sciences Volume: 18 Issue: 1 Pages: 1-13
  • DOI: 10.3390/ijms18010012
  • Peer Reviewed / Open Access
• [Remarks] 東海大学医学部臨床薬理学ホームページ
  • URL: https://www.cp-tokai.com/
• [Remarks] 東海大学医学部臨床薬理学ホームページ
  • URL: http://www.cp-tokai.com/