Because aberrant terminal differentiation is a prominent feature of myelodysplastic syndromes (MDS), these disorders have been targets of a variety of attempts to effect differentiation using non-cytotoxic agents. Derivatives of butyric acid hold promise as clinically useful differentiating agents. Sodium phenyl butyrate (PB) can effect terminal differentiation in a variety of cell lines and inhibits proliferation of primary bone marrow samples from patients with acute myelogenous leukemia (AML). Cell cycle arrest may be an important first step in differentiation pathways. This research proposal aims to test the ability of butyrate derivatives to effect differentiation in myeloid disorders, with a clinical focus on MDS. A series of clinical trials will begin with Phase I studies of PB. Activity will be sought primarily through laboratory-based endpoints. If PB appears promising, this agent will be further developed in combination with other differentiating agents such as myeloid growth factors and retinoids. If adequate serum levels of PB are not attainable, further clinical studies with other butyric acid derivatives will be pursued.
The Specific Aims address the overall question: Do clinically achievable levels of PB effect differentiation in MDS and AML? Specific Aim 1 consists of a Phase I trial of PB in MDS and relapsed AML with pharmacokinetics targeting the ID50 for inhibition of proliferation of AML cells. In addition to the pharmacokinetic endpoints, clinical progress will be monitored, and laboratory investigations will be pursued. These laboratory studies will look at the effects of PB on the proliferation, differentiation, and apoptosis of bone marrow CD34+ cells. Bone marrows will also be studied for impact of PB on colony forming units and bone marrow clonality.
Specific Aim 2 will be a subsequent Phase I trial of PB, examining the feasibility of prolonged infusions of PB, as prolonged exposure to differentiating agents may be necessary for efficacy. This trial will focus on the laboratory endpoints begun in the first trial to look for laboratory evidence of biological effect. Because the PB infusions will be prolonged, the kinetics of changes in laboratory endpoints will also be examined.
In Specific Aim 3, bone marrows from patients treated with PB will be examined ex vivo to determine whether treatment with PB impacts on the sensitivity of myeloid progenitor cells to other differentiating agents, including growth factors and retinoids. These studies will help direct further development of PB and other butyric acid derivatives as differentiating agents in myeloid disorders.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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