TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS

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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.