TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS

慢性粒细胞白血病(CML)是一种起源于多能造血干细胞的恶性肿瘤。只有20%-25%的CML患者有资格接受异基因骨髓移植的根治性治疗，接受这种治疗的患者中只有大约一半将是长期幸存者。BCR-ABL融合蛋白存在于95%的CML患者中，被认为是这种疾病的原因。由于ABL的酪氨酸激酶活性是BCR-ABL融合蛋白转化功能所必需的，因此ABL酪氨酸激酶的特异性抑制剂似乎是治疗这种疾病的理想药物。我们一直在评估一种特定的ABL酪氨酸激酶抑制剂作为这种疾病的治疗剂。该抑制物对bcr-abl阳性细胞具有特异性杀伤作用，并能在CML患者样本集落形成试验中筛选出bcr-abl阴性造血祖细胞。体内对表达bcr-abl的肿瘤也有抗肿瘤活性。动物毒理学显示高剂量的肝脏炎症，伴有轻微的骨髓抑制、贫血和移行细胞增生。这种化合物的I期临床试验已经开始在干扰素治疗失败的CML患者身上进行。这项提议的目标是完成我们对CML患者的第一阶段临床试验，并启动对CML和其他恶性肿瘤的第二阶段试验。建议进行其他实验，以优化BCR-ABL阳性造血祖细胞的体外净化条件，以结合我们正在进行的针对CML患者的自体骨髓移植方案。如果在我们的第一阶段试验中观察到这种化合物的过度毒性，这将提供一种替代治疗策略。此外，还将对ABL酪氨酸激酶抑制剂的作用机制进行结构分析。这一信息将有助于设计更有效和更特异的ABL激酶抑制剂，并将有助于设计其他酪氨酸激酶的抑制剂。

Chronic myelogenous leukemia (CML) is a malignancy arising from a pluripotent hematopoietic stem cell. Only 20-25 percent of patients with CML are eligible for curative therapy with an allogeneic bone marrow transplant and only about half of the patients undergoing this therapy will be long term survivors. The BCR-ABL fusion protein, present in 95 percent of patients with CML, has been implicated as the cause of this disease. As the tyrosine kinase activity of ABL is required for the transforming function of the BCR-ABL fusion protein, a specific inhibitor of the ABL tyrosine kinase would seem an ideal therapy for this disorder. We have been evaluating a specific ABL tyrosine kinase inhibitor as a therapeutic agent for this disease. This inhibitor exhibits specific killing of BCR-ABL positive cell lines and is capable of selecting for BCR-ABL negative hematopoietic progenitor cells in colony forming assays of CML patient samples. In vivo antitumor activity against BCR-ABL-expressing tumors has also been demonstrated. Animal toxicology demonstrated hepatic inflammation at high doses along with mild myelosuppression, anemia, and transitional cell hyperplasia. Phase I clinical trials of this compound have begun in CML patients who have failed Interferon therapy. The goals of this proposal are to complete our Phase I clinical trials in CML patients and initiate Phase II trials in CML and other malignancies. Other experiments are proposed to optimize the conditions for in vitro purging of BCR-ABL positive hematopoietic progenitors to combine with our ongoing autologous bone marrow transplantation protocol for CML patients. This would provide an alternative treatment strategy if excess toxicity from this compound is observed in our Phase I trials. In addition, a structural analysis of the mechanism of action of the ABL tyrosine kinase inhibitor will be performed. This information would be useful for the design of more potent and specific ABL kinase inhibitors and would be helpful in the design of inhibitors of other tyrosine kinases.