Nucleoside Transporter-Connexin Interplay in Pancreatic Cancer Chemotherapy

对核苷类似物(如吉西他滨)的抗药性是其主要潜在原因之一 胰腺癌极差的预后状态。而细胞核苷反式转运蛋白的关键作用。 转运蛋白(NTS)和细胞间隙连接蛋白(CXS)在确定核苷对肿瘤暴露中的作用 药物已经开始出现，它们在确定核苷类似物化疗敏感性和 它们在预测化疗反应方面的潜力尚不清楚。我们的长期目标是改善 胰腺癌的化疗管理。此R15应用程序的总体目标是投资- GATE NT-CX在胰腺癌化疗中的相互作用中心假设是NT-Cx的类型 表达的结合将决定化疗敏感性，然后特定的结合(S)可以成为靶点 提高抗肿瘤疗效。这一假说是在连续研究的基础上提出的。 关于NTS和CXS及其在PAN和CX亚型中发现的非遗传性功能改变 克雷格肿瘤。这项拟议的研究的基本原理是，理解准确的决定因素 核苷类似物的敏感性将有助于预先选择适合这种治疗类型的患者和 确定临床策略以提高对不良反应者的疗效。具体目标1将定义 NT-CX组合在核苷类似物化疗敏感性中的作用。工作假设是吉西他滨细胞- 在表达集中的NT-1(HCNT1)-Cx32组合的细胞中，毒性将更强，而化疗-1(HCNT1)-Cx32-Cx32的联合作用 由于一个元件的损失而产生的阻力可以由另一个元件有效地补偿。这一假设是 目的：探讨NTS和CXS在胰腺肿瘤中的表达和渗透特性。具体目标2 将确定调控NT-CX相互作用的调节剂，以提高化疗敏感性。工作假说是 通过操纵NT-CX组合以增加药物暴露，可以实现有利的操纵。 最新的钙粘附素或microRNA。这一假设是基于申请者的研究表明，钙粘素控制 Cx组装和microRNAs作为hCNT1的可能调节因子。《特效靶向3》将研究体内的预 使用NT-CX组合的核苷类似物响应的可判断性。工作假设是，一个公司-- 由特异性NTS和CXS组成的部位指数比前两者更能预测吉西他滨在体内的反应。 列出单一指数(即，仅平衡NT 1(HENT1))。这一假设是基于Pre-Pre的外推 在培养的胰腺癌细胞中获得的初步体外结果。这项工作的预期成果是 NT-CX在核苷类似物化疗敏感性中的相互作用及提高NT-CX敏感性的策略 介导性药物靶向和预测化疗反应的临床措施的评价 胰腺癌亚型。这种方法是创新的，因为它侧重于 判断化疗反应。这一贡献意义重大，因为它将使后续的翻译- 有望改善胰腺癌患者治疗和生存结果的常规研究。

Chemoresistance to nucleoside analog drugs (e.g., gemcitabine) is one of the main underlying reasons for the extremely poor prognostic state of pancreatic cancer. While the pivotal roles of cellular nucleoside trans- porters (NTs) and intercellular gap junctional connexins (Cxs) in determining tumor exposure of nucleoside drugs have begun to emerge, their functional interplay in determining nucleoside analog chemosensitivity and their potential in predicting response to chemotherapy remain unknown. Our long-term goal is to improve the chemotherapeutic management of pancreatic cancer. The overall objective of this R15 application is to investi- gate NT-Cx interplay in pancreatic cancer chemotherapy. The central hypothesis is that the type of NT-Cx combination expressed will dictate chemosensitivity and that the specific combination(s) can then be targeted to increase anti-tumor efficacy. This hypothesis has been formulated on the basis of the continuum of studies on NTs and Cxs and the recent discovery of non-genetic functional alterations in NT and Cx subtypes in pan- creatic tumors. The rationale underlying the proposed research is that understanding the precise determinants of nucleoside analog sensitivity will help in the preselection of patients suitable for this type of therapy and the identification of clinical strategies to increase efficacy in poor responders. Specific aim 1 will define the role of NT-Cx combinations in nucleoside analog chemosensitivity. The working hypothesis is that gemcitabine cyto- toxicity will be superior in cells expressing the concentrative NT 1 (hCNT1)-Cx32 combination, and that chemo- resistance due to the loss of one component can be effectively compensated by the other. This hypothesis is based on the expression and permeation characteristics of NTs and Cxs in pancreatic tumors. Specific aim 2 will determine the regulators governing NT-Cx interplay to improve chemosensitivity. The working hypothesis is that the favorable manipulation of NT-Cx combinations to increase drug exposure can be achieved by manipu- lating cadherins or microRNAs. This hypothesis is based on the applicant's studies showing cadherin control of Cx assembly and microRNAs as putative regulators of hCNT1. Specific aim 3 will investigate the in vivo pre- dictability of nucleoside analog response using NT-Cx combinations. The working hypothesis is that a compo- site index comprising of specific NTs and Cxs will better predict in vivo gemcitabine response than with the ex- isting single index (i.e., equilibrative NT 1 (hENT1) alone). This hypothesis is based on the extrapolation of pre- liminary in vitro results obtained in cultured pancreatic cancer cells. The anticipated outcomes of this work are the delineation of NT-Cx interplay in nucleoside analog chemosensitivity, strategies to improve NT-Cx- mediated drug targeting, and evaluation of clinical measures for predicting chemotherapeutic responses in pancreatic cancer subtypes. This approach is innovative because it focuses on a comprehensive index for judging chemotherapeutic response. This contribution is significant because it will enable subsequent transla- tional studies that are expected to improve treatment and survival outcomes in pancreatic cancer patients.