CXCR4 antagonists in acute lymphoblastic leukemias in NOD/SCID mice

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。这些病人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是ALL细胞生长和存活的主要调节因子。它是目前已知的唯一能显著刺激大多数ALL患者细胞生长存活的因子。SDF-1受体CXCR4的特异性拮抗剂是可用的。通过使用这些拮抗剂来剥夺ALL细胞中的SDF-1，为治疗ALL提供了一种全新的方法。CXCR4拮抗剂也会增加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，而这些分子本身几乎没有作用。了解SDF-1的潜在作用机制及其协同作用的因素将有助于该方法的进一步发展。该项目将研究CXCR4拮抗剂对调节ALL细胞生长和存活的蛋白表达的调节，为CXCR4拮抗剂如何工作提供见解。该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动物模型。这些拮抗剂将单独进行测试，并与目前使用的化疗药物联合进行测试。正如我们在实验室培养中所看到的那样，预计CXCR4拮抗剂将抑制ALL细胞的生长，并增加它们对化疗药物的敏感性。在目前的治疗方案中加入CXCR4拮抗剂有望显著改善患者的预后。

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.