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교모세포종 세포주 및 이식종양 모델에서 DNA Methyltransferase 억제제인 신합성 Phthalimido-alkanamide 유도체의 방사선감수성 증강효과 및 기전
Full text link학위논문(박사)--서울대학교 대학원 :의과대학 의학과,2019. 8. 김일한.Background and purpose: Radiotherapy is an essential element for treating glioblastoma, the most common malignant adult brain tumor harboring devastating prognosis. Strategies to enhance the therapeutic ratio of radiotherapy in glioblastoma are warranted. Our aim is to report a novel DNA methyltransferase inhibitor as a potential radiosensitizing agent in glioblastoma.
Materials and Methods: Four glioblastoma cell lines (U87MG, U373MG, U138MG, and T98G) and one normal astrocyte cell line (NHA) were used. Radiosensitizing effects of a newly synthesized phthalimido-alkanamide derivative, MA17, were assessed in these cells using clonogenic assay. 6MV X-rays were used for irradiation of cells and pretreatment with MA17 was done for cells treated by combined treatment. We performed a tumor growth delay assay with two glioblastoma lines (U87MG and U138MG) using BALB/C-nude mice. We also evaluated DNA methyltransferase (DNMT) inhibition, apoptosis, autophagy, DNA damage repair, and FANCA expression. Tissue-to-plasma partition coefficient of MA17 was obtained to evaluate blood-brain barrier penetration and distribution in brain tissues.
Results: MA17 significantly radiosensitized all glioblastoma cells in vitro with mean sensitizer enhancement ratios of 1.196 (p=0.034), 1.441 (p=0.029), 1.152 (p=0.030), and 1.350 (p<0.001) at a surviving fraction of 0.2 for U87MG, U373MG, U138MG, and T98G cells, respectively. However, MA17 did not affect the radiosensitivity of NHA cells with mean sensitizer enhancement ratio of 1.016 (p=0.420). The mean tumor doubling time in vivo in cells treated with irradiation+MA17, compared to irradiation alone, was prolonged by a margin of 6.35 days (p=0.009) and 3.06 days (p=0.030) in U87MG and U138MG cells, respectively. Western blotting revealed that DNMT1/DNMT3A/DNMT3B activity is down-regulated, and apoptosis/autophagy are induced by MA17. Double-stranded DNA break foci were observed for prolonged periods in cells treated with MA17 in all 4 glioblastoma cell lines. FANCA expression was also inhibited by MA17. The tissue-to-plasma partition coefficient was unquantifiable indicating inability of MA17 to cross the blood-brain barrier.
Conclusion: We first evaluated a novel phthalimido-alkanamide derivative, MA17, as a potential radiosensitizer in human glioblastoma cells. MA17 demonstrated significant radiosensitization in glioblastoma cells in vitro and in vivo. Radiosensitization was associated with induction of apoptosis and autophagy, as well as suppression of DNA damage repair and FANCA expression. Further investigation is needed to translate these results to the clinic.배경 및 목적: 교모세포종은 성인에서 가장 흔한 원발성 뇌종양이다. 하지만 핵심적 치료기법인 수술-방사선요법의 발전에도 불구하고 예후는 극히 불량하다. 이에 본 연구를 통해 DNA methyltransferase를 억제하는 십합성 phthalimido-alkanamide 유도체가 교모세포종에서 세포에서 방사선감수성 증강 효과가 있는지 및 그 기전이 무엇인지를 규명하기로 하였다.
방법: 총 4종류의 인간 교모세포종 세포주(U87MG, U373MG, U138MG, T98G)와 1종류의 인간 정상 별아교세포 세포주 (NHA)를 배양하여 사용하였다. 신합성된 phthalimido-alkanamide 유도체인 MA17의 방사선감작효과는 세포집락형성능력을 기준으로 한 세포생존을 기본지표로 평가하였다. 방사선은 6MV 엑스선을 사용하였고 약물병용시에는 MA17을 방사선조사전 24시간동안 전처치하였다. 또한 방사선감작의 기전을 규명하기 위하여 DNA methyltransferase의 (DNMT) 억제, 세포고사, 자가포식, DNA 손상 회복, FANCA 발현 정도를 측정하였다. 모든 in vitro 실험은 독립적으로 3회 실시하였다. In vivo에서 방사선감작효과를 평가하기 위하여 2종류의 세포주를 (U87MG와 U138MG) BALB/C-nude 마우스의 등에 이식하였고, 방사선조사후 종양성장지연측정 방법을 통하여 MA17의 in vivo 방사선감작효과를 평가하였다. 또한 MA17이 혈뇌장벽을 통과하여 뇌조직에 분포할 수 있는지를 평가하기 위해 조직-혈장 분배계수를 측정하였다.
결과: In vitro에서 MA17은 4종류의 교모세포종 세포주 모두에서 유의한 방사선감작효과를 나타내었다. 생존분획 0.2에서의 평균 방사선효과증강율은 U87MG, U373MG, U138MG, T98G 세포에서 각각 1.196 (p=0.034), 1.441 (p=0.029), 1.152 (p=0.030), 1.350이었다 (p<0.001). 그러나 MA17은 정상 별아교세포 세포주에서는 평균 방사선효과증강율 1.016으로 (p=0.420) 방사선민감도에 영향을 주지 않았다. In vivo 종양성장지연측정 실험에서도 방사선조사와 MA17을 병용한 군에서 방사선조사 단독 군에 비하여 종양배가시간이 U87MG과 U138MG 종양에서 각각 6.35일과 (p=0.009) 3.06일씩 (p=0.030) 증가하였다. Western blot에서는 MA17이 DNMT1/DNMT3A/DNMT3B 활동도를 저해하고 세포고사 및 자가포식를 유도한다는 것을 확인하였다. 또한 MA17에 의해 4종류의 교모세포종 세포주에서 DNA 이중 가닥 절단의 복구가 지연되고 및 FANCA 단백질 발현이 억제됨을 확인하였다. MA17의 조직-혈장 분배계수는 검출한계 미만으로 도출되어, MA17은 혈뇌장벽을 통과하여 뇌조직에 분포하지 않는 것으로 나타났다.
결론: 본 연구는 교모세포종에서 신합성 phthalimido-alkanamide 유도체인 MA17이 지닌 방사선감작효과를 확인한 첫번째 연구이다. In vitro와 in vivo 모두에서 MA17은 유의한 방사선감작효과를 보였다. 그 기전으로는 MA17에 의한 세포고사 및 자가포식 유발과 DNA 손상회복 및 FANCA 단백질 발현억제 등이 관여하는 것으로 확인되었다. 이 신약의 임상적용은 추가연구가 필요할 것으로 보인다.Abstract i
Contents iv
List of Tables v
List of Figures vi
Introduction 1
Materials & Methods 7
Results 15
Discussion 46
References 53
Abstract in Korean 60Docto
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No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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