Antisense PNA-PEG conjugate targeting a single nucleotide mutation in K-ras gene induces cell apoptosis in pancreatic cancer cells
| Project/Area Number |
16K05917
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Polymer/Textile materials
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| Research Institution | Tottori University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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| Keywords | 難治性がん疾患 / 遺伝子治療薬 / ペプチド核酸 / 遺伝子発現制御 / KRAS遺伝子 / KRAS遺伝子変異 / 遺伝子発現抑制 / SNP / がん治療 / 人工核酸 / 遺伝子変異 / 1塩基変異 |
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| Outline of Final Research Achievements |
For the development of an antisense nucleic acid therapy, we synthesized the inchworm-type peptide nucleic acid (PNA)-polyethylene glycol (PEG) conjugate with oligoarginine (i-PPC(R9)) as a cell-penetrating peptide, and evaluated cell death by i-PPC(R9) for pancreatic cancer cells (BxPC-3 cells) without mutation (wild type: GGT) and PANC-1 cells with a single nucleotide KRAS mutation (mutant type: GAT) of codon 12. As a results, i-PPC(R9) was transported into the cytoplasm of cells, and compared with i-PPC(R9)_AT having a random base sequence consisting of adenine (A) and thymine (T), which is not complementary to the sequence of KRAS codon 12, apotosis-mediated cell death was induced in BxPC-3 cells (20 %) and PANC-1 cells (10 %) by full-muched i-PPC(R9) to KRAS codon 12, respectively. It indicated that the gene expression can be controlled by i-PPC(R9) depended on a point mutation of KRAS gene in cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
KRAS遺伝子点突然変異はすい臓がん患者の90％，大腸がん患者の40～50％，肺線がんの20～30%，肛門部胆管がんの50％など実に多くの臓器がんで認められており，この変異が原因となって最新の分子標的薬（抗EGFR抗体薬）の薬効が期待できない問題点を引き起こしている。変異型KRASの機能・発現抑制により副作用を伴わないがん治療が期待できるが，現時点ではこのような遺伝子治療薬は開発されていない。
本研究ではこれらの遺伝子変異を対象とした新たな人工遺伝子を作製した結果，細胞レベルの評価では一定の薬効特性を示すことが証明された。今後は，具体的な遺伝子治療薬としての展開が期待される。
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted 5,6-Dehydro-1,3-dimethyluracils and Their Transformation to 6-Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils and 4,5,5-Trisubstituted 3-Methyloxazolizin-2-ones2016
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