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首页> 外文学位 >Cellular uptake of cobalamin in clinically-derived blood samples, normal and cancerous brain cells.
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Cellular uptake of cobalamin in clinically-derived blood samples, normal and cancerous brain cells.

机译：临床上采集的血样，正常和癌性脑细胞中钴胺素的细胞摄取。

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摘要

The cellular uptake and sequestration of fluorescently labeled cobalamin by cancer cells and normal cells was studied by fluorescence flow cytometry and fluorescence microscopy. A fluorescent analog of cobalamin was synthesized by attaching the Oregon Green 488RTM fluorophore to the cobalt atom of cobalamin.;The sequestration of cobalamin by 35 blood samples from patients with myeloid leukemia was quantified by flow cytometry. Blood samples from patients with the M1-subtype of acute myelogenous leukemia exhibited the most aggressive uptake and sequestration of cobalamin. Less uptake of fluorescent cobalamin was exhibited by the M2, M3 and M4/M5 subtypes of leukemia cells that have increasing levels of cellular maturation. This is consistent with the hypothesis that cancer cells that are closer to progenitor cells will have the greatest demand for cobalamin.;The uptake of fluorescent cobalamin by human astrocytes and T98G human glioblastoma cells was quantified by confocal fluorescence microscopy and flow cytometry. Neoplastic glioblastoma cells sequester more fluorescent cobalamin than normal astrocytes. Cobalamin-targeted delivery of cytotoxic drugs may be a useful method to treat brain tumors.;The cellular pharmacokinetic behavior of four naturally-occurring forms of cobalamin was studied to determine the form of cobalamin with the longest mean-residence-time in cells. Methylcobalamin exhibited a shorter mean residence time than adenosylcobalamin or cyanocobalamin in all cell types.;The reaction of amyl nitrite with naturally-occurring forms of cobalamin was studied. The co-morbidity of amyl nitrite abuse with the development of AIDS and Kaposi's sarcoma has yet to be explained. Amyl nitrite reacts rapidly with hydroxocobalamin and methylcobalamin, but no reaction with adenosylcobalamin and cyanocobalamin could be detected. The depletion of free methylcobalamin and hydroxocobalamin in blood is consistent with the suggestion that methylcobalamin may play a role in regulation of the innate immune system.;The ability of cobalamin to deliver a pentapeptide from the N-terminus of the apoptosis-activating protein, Smac, was investigated. Cobalamin was not an effective delivery vehicle for the AIPVA pentapeptide, as premature cleavage of the peptide occurs in lysosomes.
机译：通过荧光流式细胞术和荧光显微镜研究了癌细胞和正常细胞对荧光标记钴胺素的细胞摄取和隔离。通过将Oregon Green 488RTM荧光团附着到钴胺素的钴原子上来合成钴胺素的荧光类似物;通过流式细胞术对35例髓样白血病患者的血样中钴胺素的螯合进行定量。患有急性髓性白血病M1亚型的患者的血液样本显示出钴胺素的摄取和隔离最为积极。具有逐渐成熟的细胞水平的白血病细胞的M2，M3和M4 / M5亚型对荧光钴胺素的吸收较少。这与以下假设相吻合：更接近祖细胞的癌细胞对钴胺素的需求最大。通过共聚焦荧光显微镜和流式细胞术对人星形胶质细胞和T98G人胶质母细胞瘤细胞对荧光钴胺素的吸收进行了定量。肿瘤性胶质母细胞瘤细胞比正常星形胶质细胞螯合更多的荧光钴胺素。以钴胺素为靶点的细胞毒性药物的递送可能是治疗脑肿瘤的一种有用方法。研究了四种天然形式的钴胺素的细胞药代动力学行为，以确定在细胞中平均停留时间最长的钴胺素的形式。在所有细胞类型中，甲基钴胺素的平均停留时间均比腺苷钴胺素或氰基钴胺素短。;研究了亚硝酸戊酯与天然形式的钴胺素的反应。亚硝酸戊酯滥用与艾滋病和卡波济氏肉瘤的发展并存的现象尚未得到解释。亚硝酸戊酯与羟考巴胺和甲基钴胺素反应迅速，但未检测到与腺苷钴胺素和氰钴胺素的反应。血液中游离甲基钴胺素和羟考巴胺的消耗与以下暗示相符：甲基钴胺素可能在先天免疫系统的调节中发挥作用。钴胺素从凋亡激活蛋白Smac的N末端释放五肽的能力。 ，进行了调查。钴胺素不是AIPVA五肽的有效递送载体，因为该肽的过早裂解发生在溶酶体中。

著录项

  • 作者

    Shi, Yao.;

  • 作者单位

    The University of Utah.;

  • 授予单位 The University of Utah.;
  • 学科 Chemistry Analytical.;Chemistry Pharmaceutical.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 205 p.
  • 总页数 205
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;生物化学;药物化学;
  • 关键词

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