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）：获得性多药耐药性（MDR）的发展是癌症化疗的主要挑战。 可能的机制包括高水平的 mdr 1p-糖蛋白以及谷胱甘肽转移酶 (GST) 和谷胱甘肽 (GSH) 修复机制。 但这两种机制都无法解释获得性耐多药的广谱性质。 细胞凋亡变阻器向生存方向的改变可以解释通过不同作用机制诱导细胞凋亡的药物之间的交叉耐药性。 这些机制的临床相关性尚不清楚，因为使用 Pgp 或 GS​​H 抑制剂或 Bcl-2 反义药物的研究尚未改善化疗的疗效或尚未完成。 我们最近证明，实体瘤中表达的两种成纤维细胞生长因子，即酸性和碱性 FGF（aFGF 和 bFGF），可诱导对不同结构和作用机制的药物产生广谱耐药性（高达 10 倍）。 FGF 与其受体结合的抑制剂，包括单克隆抗体和/或苏拉明，可以完全逆转外源性 FGF 诱导的耐药性。 我们进一步发现，无毒和亚治疗剂量的苏拉明可增强紫杉醇和阿霉素对携带人类异种移植物的小鼠的疗效。 I期试验的初步结果还表明，苏拉明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，使得治疗后的FGF水平足以诱发耐药性。 FGF 水平提高是由于 FGF 产生和分泌增加，以及细胞裂解时蛋白质释放增加。 苏拉明逆转了培养细胞和异种移植物中药物治疗诱导的耐药性。 最后，cDNA 微阵列结果表明，bFGF 处理改变了 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，加上表明 bFGF 增强 GST 并使细胞凋亡变阻器转向生存的文献数据，使我们推测药物治疗会诱导 FGF 水平增加，进而导致获得性 MDR，并且获得性 MDR 可以是FGF抑制剂可以克服这一问题。 这四个目标如下。 (1) 确定药物治疗可提高细胞外 FGF 水平。 (2) 检验 FGF 诱导导致获得性 MDR 的假设。 (3) 检验以下假设：FGF 是触发获得性 MDR 的几种已知机制的上游事件。 (4)在体外和体内条件下检验苏拉明可以逆转获得性MDR的假设。