Stromal modulation of response to Thymidylate synthase inhibitors

摘要 抗癌治疗通常针对的是肿瘤细胞。该酶的抑制剂 胸腺嘧啶酸合成酶(TS)，特别是氟代嘧啶类化合物，已在临床上使用多年。 治疗多种癌症。尽管在遗传和分子方面进行了广泛的研究 影响肿瘤对TS抑制剂反应的因素，其临床疗效仍然有限。在这个项目中，我们 提出一种新的方法来提高肿瘤对这些药物的反应。肿瘤浸润性的是一种 非肿瘤细胞的异质性群体。这些细胞包括宿主来源的细胞，如成纤维细胞， 巨噬细胞、淋巴细胞、内皮细胞等与细胞外基质共同构成肿瘤 基质或微环境。通过分泌一系列细胞因子、生长因子、荷尔蒙等，它们发挥着 在肿瘤生长和进展中的关键作用，以及对治疗剂的反应。在这份提案中， 我们将检验这样一种假设，即肿瘤对TS抑制剂的反应是由以下药物的化疗敏感性决定的 浸润性基质细胞。我们将利用ApcMin/+鼠标，这是易于开发的 小肠和结肠腺瘤性肿瘤。通过骨髓移植，我们将产生 其中基质细胞的化疗敏感性与肿瘤不同的嵌合小鼠。我们预测 这些小鼠的肿瘤将表现出反映基质细胞化疗敏感性的药物反应。 根据初步结果，Aim 1将确定TS抑制剂对基质细胞的影响 间隔室，以确定对TS抑制剂反应的间质介质。目标2，将检查TS的效果 间质细胞下调肿瘤对TS抑制剂的反应。在目标3中，我们将引导敏化到 针对肿瘤相关间质细胞的TS抑制剂。总而言之，在这个项目中测试的假设 将为利用基质细胞改进治疗方法的新治疗模式的开发铺平道路 靶向肿瘤细胞，确保药物诱导的癌细胞死亡。

ABSTRACT Anti-cancer therapy has typically been targeted on neoplastic cells. Inhibitors of the enzyme thymidylate synthase (TS), particularly fluoropyrimidines, have been used for many years in the clinical management of a variety of cancers. In spite of the extensive research on the genetic and molecular factors governing tumor response to TS inhibitors, its clinical efficacy remains limited. In this project, we propose a novel approach to increase tumor response to these agents. Tumors are infiltrated with a heterogeneous population of non-neoplastic cells. These include host-derived cells such as fibroblasts, macrophages, lymphocytes, endothelial cells, etc. Together with extracellular matrix, make up the tumor stroma or microenvironment. By secreting an array of cytokines, growth factors, hormones, etc., they play a critical role in tumor growth and progression, as well as response to therapeutic agents. In this proposal, we will test the hypothesis that tumor response to TS inhibitors is governed by the chemosensitivity of infiltrating stromal cells. We will utilize the ApcMin/+ mouse which is predisposed to the development of adenomatous tumors of the small intestine and the colon. By bone marrow transplantation we will generate chimeric mice wherein the chemosensitivity of stromal cells is distinct from that of the tumor. We predict that tumors in these mice will show a drug response that reflects the chemosensitivity of stromal cells. Based on preliminary results, Aim 1 will determine the impact of TS inhibitors on cells in the stromal compartment to identify stromal mediators of response to TS inhibitors. Aim 2, will examine the effect of TS down regulation in stromal cells on tumor response to TS inhibitors. In Aim 3, we will direct sensitization to TS inhibitors specifically to tumor associated stromal cells. In all, the hypothesis being tested in this project will pave the way for development of new treatment modalities using stromal cells to improve therapies targeted at tumor cells to ensure drug induced cancer cell death.