FGF: A Mechanism of Acquired Multidrug Resistance

FGF：获得性多药耐药性的机制

• 批准号: 6530410
• 负责人: Jessie L.-S. Au
• 金额: $ 24.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530410
• 关键词: DNA topoisomerases; acidity /alkalinity; apoptosis; athymic mouse; cell line; clinical research; enzyme linked immunosorbent assay; fibroblast growth factor; gene expression; glutathione transferase; growth factor receptors; human tissue; image processing; immunocytochemistry; monoclonal antibody; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; pharmacokinetics; suramin; xenotransplantation

DESCRIPTION (provided by applicant): Development of acquired multidrug resistance (MDR) is a major challenge in cancer chemotherapy. The possible mechanisms include high levels of mdr 1p-glycoprotein and the glutathione transferase (GST) and glutathione (GSH) repair mechanism. But neither mechanism explains the broad-spectrum nature of acquired MDR. Alteration of the apoptosis rheostat toward survival could explain the cross resistance among drugs that induce apoptosis through different action mechanisms. The clinical relevance of these mechanisms is not known as studies using Pgp or GSH inhibitors or antisense to Bcl-2 have not improved the efficacy of chemotherapy or have not been completed. We recently demonstrated that two fibroblast growth factors, i.e., acidic and basic FGF (aFGF and bFGF) that are expressed in solid tumors, induce a broad-spectrum resistance (up to 10-fold) to drugs with diverse structures and action mechanisms. Inhibitors of FGF binding to their receptors, including monoclonal antibodies and/or suramin, completely reverse the resistance induced by exogenous FGF. We further found that nontoxic and subtherapeutic doses of suramin enhance the efficacy of paclitaxel and doxorubicin in mice bearing human xenografts. Preliminary results of a phase I trial also suggest that suramin enhanced the efficacy of paclitaxel and carboplatin non-small cell lung cancer patients. Additional preliminary results indicate that short term (72 hour) and long-term (6 months) drug treatments enhanced the levels of intracellular and/or extracellular aFGF and bFGF, under in vitro and in vivo conditions, such that the post-treatment FGF levels were sufficient to induce drug resistance. The enhanced FGF levels were due to increased FGF production and secretion, and release of protein upon cell lysis. Drug treatment-induced resistance in cultured cells and xenografts was reversed by suramin. Finally, cDNA microarray results show that bFGF treatment altered the expression of GST, Bcl-2 family proteins, drug efflux proteins, and topoisomerases. These preliminary results, together with the literature data indicating that bFGF enhances GST and shifts the apoptosis rheostat toward survival, have led us to hypothesize that drug treatment induces increases in FGF levels, which in turn lead to acquired MDR, and that acquired MDR can be overcome by FGF inhibitors. The four Aims are as follows. (1) Establish that drug treatment enhances extracellular FGF levels. (2) Test the hypothesis that the FGF induction results in acquired MDR. (3) Test the hytpothesis that FGF is an upstream event that triggers several known mechanisms of acquired MDR. (4) Test the hypothesis that suramin can reverse acquired MDR under in vitro and in vivo conditions.

描述（由申请人提供）：获得的多药耐药性（MDR）的发展是癌症化学疗法的主要挑战。 可能的机制包括高水平的MDR 1P-糖蛋白，谷胱甘肽转移酶（GST）和谷胱甘肽（GSH）修复机制。 但是，这两种机制都解释了获得的MDR的广泛性质。 细胞凋亡对生存的改变可以解释通过不同的作用机制诱导凋亡的药物之间的跨阻力。 这些机制的临床相关性不被称为使用PGP或GSH抑制剂或对Bcl-2反义的研究，但没有提高化学疗法的疗效或尚未完成。 我们最近证明，在实体瘤中表达的两个成纤维细胞生长因子，即酸性和碱性FGF（AFGF和BFGF），诱导具有多种结构和动作机制的药物的广谱耐药性（多达10倍）。 FGF与其受体结合的抑制剂，包括单克隆抗体和/或苏拉蛋白，完全逆转了外源性FGF诱导的耐药性。 我们进一步发现，苏拉米蛋白的无毒和亚治性剂量增强了紫杉醇和阿霉素在携带人异种移植物的小鼠中的疗效。 第一阶段试验的初步结果还表明，苏拉米蛋白增强了紫杉醇和卡铂非小细胞肺癌患者的疗效。 其他初步结果表明，在体外和体内条件下，短期（72小时）和长期（6个月）药物治疗增强了细胞内和/或细胞外AFGF和BFGF的水平，以使治疗后的FGF水平足以诱导耐药性。 FGF水平增强是由于FGF产生和分泌增加以及细胞裂解后蛋白质释放所致。 药物治疗诱导的培养细胞和异种移植物的耐药性被苏拉蛋白逆转。 最后，cDNA微阵列结果表明，BFGF治疗改变了GST，BCL-2家族蛋白，药物外排蛋白和拓扑异构酶的表达。 这些初步结果与文献数据一起表明，BFGF增强了GST并将凋亡的凋亡变性转移到生存中，这使我们假设药物治疗诱导FGF水平的增加，从而导致获得的MDR，并且FGF抑制剂可以克服获得的MDR。 四个目标如下。 （1）确定药物治疗会增强细胞外FGF水平。 （2）检验了FGF诱导导致获得的MDR的假设。 （3）测试FGF是上游事件的杂种，它触发了获得的MDR的几种已知机制。 （4）检验以下假设：在体外和体内条件下，苏拉米蛋白可以逆转MDR。