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首页> 外文学位 >Role of equilibrative nucleoside transporters 1 and 2 in the transport and disposition of gemcitabine and its metabolites in cervical carcinoma .
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Role of equilibrative nucleoside transporters 1 and 2 in the transport and disposition of gemcitabine and its metabolites in cervical carcinoma .

机译：平衡核苷转运体1和2在吉西他滨及其代谢物在宫颈癌中的转运和作用。

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摘要

Gemcitabine is a nucleoside analog used as a radiosensitizer for the treatment of locally advanced cervical carcinoma. Yet, despite its efficacy when administered concomitantly with radiation, gemcitabine therapy is not without side effects. The utility of delivering gemcitabine directly to the cervix was explored through the use of a novel drug delivery device, CerviPrep(TM). Local administration to the cervix led to clinically relevant concentrations of gemcitabine in cervical tissue and plasma, while no gemcitabine was detected in the systemic circulation and no side effects were reported. Our data suggest that targeting gemcitabine delivery to the cervix can limit systemic exposure and toxicity while achieving cytotoxic concentrations of drug at the target site.;Despite its widespread use in cervical carcinoma, little is known about the disposition of gemcitabine in this tissue. As a nucleoside analog, gemcitabine is a substrate for the equilibrative nucleoside transporters (hENT), and patient response to gemcitabine therapy has been associated with the expression of these proteins. A characterization of hENT1 and hENT2 in both malignant and normal cervical tissue was undertaken, and while no effect of malignancy was observed on hENT1 protein expression, hENT2 protein was nearly three-fold higher in malignant cervical tissue when compared to normal tissue. Expression of hENT mRNA was highly variable and not associated with malignancy.;We also examined the effect of dFdU on gemcitabine disposition, as this relatively inactive metabolite is present at much higher concentrations in the plasma than gemcitabine following intravenous administration of the parent compound. We report a novel interaction between dFdU and gemcitabine whereby dFdU competes with gemcitabine for transport via hENT1 and hENT2. The presence of dFdU appears to enhance the retention of gemcitabine intracellularly leading to an increase in the amount of active gemcitabine triphosphate. As more gemcitabine is phosphorylated in the presence of dFdU, a "metabolic sink" is created, further increasing gemcitabine uptake into the cell via hENT1 and hENT2. These data suggest that both transport and intracellular metabolism are equally important components of gemcitabine disposition and cytotoxic potential, and that the presence of dFdU increases intracellular exposure to this nucleoside analog.
机译：吉西他滨是一种核苷类似物，用作放射增敏剂，用于治疗局部晚期宫颈癌。然而，尽管吉西他滨疗法与放射线同时给药具有疗效，但它并非没有副作用。通过使用新型药物递送装置CerviPrep TM，探索了将吉西他滨直接递送至子宫颈的实用性。子宫颈的局部给药导致吉西他滨在宫颈组织和血浆中的临床相关浓度，而在全身循环中未检测到吉西他滨，也没有副作用的报道。我们的数据表明，靶向吉西他滨递送至子宫颈可以限制全身暴露和毒性，同时在目标部位达到药物的细胞毒性浓度。;尽管吉西他滨广泛用于宫颈癌，但对吉西他滨在该组织中的处置知之甚少。作为核苷类似物，吉西他滨是平衡核苷转运蛋白（hENT）的底物，患者对吉西他滨治疗的反应与这些蛋白的表达有关。在恶性和正常宫颈组织中均进行了hENT1和hENT2的表征，尽管未观察到恶性对hENT1蛋白表达的影响，但与正常组织相比，hENT2蛋白在恶性宫颈组织中的含量几乎高出三倍。 hENT mRNA的表达是高度可变的，与恶性肿瘤无关。我们还研究了dFdU对吉西他滨处置的影响，因为母体化合物静脉内给药后，这种相对无活性的代谢产物在血浆中的浓度比吉西他滨高得多。我们报告dFdU和吉西他滨之间的新型相互作用，其中dFdU与吉西他滨竞争通过hENT1和hENT2的转运。 dFdU的存在似乎增强了吉西他滨在细胞内的保留，从而导致活性吉西他滨三磷酸的量增加。当更多的吉西他滨在dFdU存在下被磷酸化时，会产生“代谢库”，从而进一步增加吉西他滨通过hENT1和hENT2进入细胞的摄取。这些数据表明运输和细胞内代谢都是吉西他滨处置和细胞毒性潜力的同等重要组成部分，并且dFdU的存在会增加细胞内对该核苷类似物的暴露。

著录项

  • 作者

    Hodge, Lucy Sahr.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 184 p.
  • 总页数 184
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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