Acute myelogenous leukemia (AML) is a disease in which the accumulation of primitive nonfunctional precursor cells results in the death of 80% of patients due to bleeding and infection. Although allogeneic bone marrow transplantation is curative, only 25% of AML patients are eligible for this therapy, and only half of these survive long-term. Another 10-20% of patients are cured by combination chemotherapy. In order to develop new and improved directions of therapy for AML, we are proposing to use cell cycle regulatory molecules such as growth factors or differentiation induction agents to specifically sensitize the leukemia cells to phase-specific chemotherapy agents. These treatment programs will be linked to laboratory assays which will provide short-term molecular endpoints for the evaluation of response and minimal residual disease. The molecular changes found in these leukemia cells will be used as targets for therapy as well as for predictors of response, remission duration and survival. We will carry this analysis out in untreated patients and in patients who are in remission and relapse. We will classify patients as to whether they develop a proliferative response, a differentiation induction response, or an apoptotic response to the combination of chemotherapy plus a cell cycle regulatory molecule. We will compare in vitro with in vivo responses. We will compare responses to chemotherapy and a cell cycle regulatory molecule in vitro and in vivo with respect to chemotherapy metabolism, cell cycle, cytoplasmic signal transduction molecules, growth factor synthesis, intranuclear growth regulatory proteins (1)53, WAF- 1/CIP-1, and Rb), Bcl-2/Bax and other members of the apoptosis family, and apoptotic and non-apoptotic mechanisms of cell death. We will use PCR and FISH assays specific for each of the chromosomally defined subsets of AML to define response to therapy, response to cell cycle regulatory - molecules, and minimal residual disease. We will use the information derived from these assays to allocate patients to specific programs of therapy. We will use this information to build sequential therapeutic programs which integrate chemotherapy with cell cycle regulatory molecules, used singly and in combinations. In this way, we hope to be able to develop therapy which is targeted to the molecular and biological defects in AML, which is less toxic to normal tissues and provides more durable remissions in all subsets of AML in untreated patients, in relapsed patients, and in the minimal residual disease setting. Because the principles of therapy are relevant to the treatment of epithelial neoplasms as well, we expect the information to be derived in this program to provide direction for improvements in solid tumor therapy as well.
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