Research Project
2896734
DESCRIPTION (Applicant's Description) The long-term goal is to improve the complete remission rate and duration of remission in patients undergoing treatment for acute myeloblastic leukemia (AML). Current chemotherapy induces complete remission in 60-75% of patients with AML. Unfortunately, in the absence of allogeneic bone marrow transplantation, the majority of patients will relapse and die of their original disease. Relapses occur due to a failure to completely eradicate the leukemic clone. Current intensive chemotherapy has reached the maximum tolerated dose and it is unlikely that new schedules of the available drugs will produce significant improvement. To improve outcome new agents are needed that are differentially toxic to leukemic cells, have minimal or no toxicity and can enhance the antileukemic activity of other chemotherapeutic agents; lovastatin is a drug with such potential. Lovastatin is a competitive inhibitor of HMG-CoA reductase. Lovastatin is cytotostatic to many tumor cell types however, AML cells from a majority of patients undergo apoptosis when exposed to Lovastatin. In a rat tumor model lovastatin synergizes with chemotherapy in disease control. Lovastatin has been used for years at low doses as cholesterol lowering agent; it is well tolerated at those doses. However, much higher doses will be required to achieve serum levels that inhibit leukemic cell growth. A phase I study of lovastatin given for one week at doses. Ranging from 445 mg/kg/d found nausea and vomiting and myopathy as the major toxicities. For the funding period of this grant we are proposing two clinical trials. The first is a phase I/II study to determine whether lovastatin has antileukemic effect in vivo and to determine the maximum tolerated dose of lovastatin when given for two week. This study will be supported by cell biology, molecular and phamacokinetic analyses. The second study will be a phase I/II study to determine whether lovastatin enhances the rate of complete remission and duration of complete remission when combined with chemotherapy. The first study will be carried out in relapsed patients with AML. The second study will be carried out in relapsed patients and poor risk patients with AML.
