CXCR4 antagonists in acute lymphoblastic leukemias in NOD/SCID mice

CXCR4 拮抗剂治疗 NOD/SCID 小鼠急性淋巴细胞白血病

• 批准号: nhmrc : 352326
• 负责人: A/Pr Linda Bendall
• 金额: $ 33.71万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/cxcr4-antagonists-acute-nodscid-mice/98461
• 关键词: CXCR4; antagonists; acute; lymphoblastic; leukemias

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival. It is currently the only known factor that significantly stimulates the growth-survival of cells from the majority of patients with ALL. Specific antagonists of the SDF-1 receptor, CXCR4, are available. Depriving ALL cells of SDF-1 by the use of these antagonists provides a radically new approach for the treatment of ALL. CXCR4 antagonists also increase the susceptibility of ALL cells to cytotoxic drugs. The mechanisms by which SDF-1 promotes ALL cell growth and survival are not known but appear to be largely due to synergistic interactions with other molecules that have little or no effect on their own. Knowledge of the underlying mechanisms of action of SDF-1 and the factors with which it synergises will facilitate for the further development of this approach. This project will examine the modulation of the expression of proteins that regulate ALL cell growth and survival by CXCR4 antagonists, providing insights into how CXCR4 antagonists work. This project will also extend our encouraging data obtained using tissue culture to an animal model of leukemia. The antagonists will be tested in isolation and in combination with currently used chemotherapy agents. It is expected that CXCR4 antagonists will inhibit the growth of ALL cells and increase their sensitivity to chemotherapy agents in the animal model as we have seen in laboratory culture. The addition of CXCR4 antagonists to current treatment protocols is expected to significantly improve the outcome for patients.

急性淋巴细胞白血病（ALL）是儿童癌症最常见的形式，也是儿童死亡的主要原因。虽然ALL通常对化疗有反应，但约25%的儿童和65%的成人ALL患者会复发。这些患者中的大多数将死于白血病。治疗ALL的新方法对于治愈这些患者是必要的。我们已经确定基质衍生因子（SDF）-1作为ALL细胞生长和存活的主要调节因子。它是目前唯一已知的能显著刺激大多数ALL患者细胞生长存活的因子。SDF-1受体CXCR 4的特异性拮抗剂是可用的。通过使用这些拮抗剂剥夺ALL细胞的SDF-1，为治疗ALL提供了一种全新的方法。CXCR 4拮抗剂也增加ALL细胞对细胞毒性药物的敏感性。SDF-1促进ALL细胞生长和存活的机制尚不清楚，但似乎主要是由于与其他分子的协同相互作用，这些分子本身几乎没有或没有影响。了解SDF-1的潜在作用机制及其协同作用的因素将有助于进一步发展这种方法。该项目将研究CXCR 4拮抗剂对调节ALL细胞生长和存活的蛋白质表达的调节，从而深入了解CXCR 4拮抗剂的工作原理。这个项目还将把我们利用组织培养获得的令人鼓舞的数据扩展到白血病的动物模型。拮抗剂将单独测试，并与目前使用的化疗药物组合。预期CXCR 4拮抗剂将抑制ALL细胞的生长，并增加其对动物模型中化疗药物的敏感性，正如我们在实验室培养中所见。在目前的治疗方案中加入CXCR 4拮抗剂有望显著改善患者的结局。