CLINICAL HISTONE DEACETYLASE INHIBITION AND RETINOIDS

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Dynamic changes in histone acetylation significantly regulate transcription of a variety of genes. Deacetylation of histones through recruitment of histone deacetylase enzymes (HDAC) appears to play an important mechanistic role in hematopoietic malignancies. Pharmacologic inhibition of HDAC may help reverse the malignant phenotype. The putative differentiating agent sodium phenylbutyrate (PB) induces histone acetylation in myeloid cells at concentrations maintained in vivo. In in vitro systems, inhibitors of HDAC synergize with retinoids in retinoid-responsive systems. Retinoids are critically important in myeloid differentiation. PB and all trans-retinoic acid (ATRA) show marked synergy in the ML-1 myeloid leukemia cell line, which has formed a foundation for pre-clinical development of PB in myeloid malignancies. The research proposed in this application begins the clinical development of the combination of PB plus ATRA in myelodysplasia (MDS) and high-risk acute myeloid leukemia (AML) through a Phase 1 study supported by correlative biological studies. The clinical feasibility and toxicity of this combination will be studied, and potential pharmacokinetic interactions between the two drugs will be investigated. Biological endpoints will be directed to determine whether administration of PB plus ATRA leads to predicted pharmacodynamic effects. These include induction of histone acetylation in peripheral blood and bone marrow mononuclear cells, induction of expression of p21WAF1/CIP1, and down-stream changes in bone marrow proliferation and differentiation. Changes in biological and clinical parameters will be correlated with pharmacokinetic measurements including steady state concentrations and area under the plasma concentration-time curve. Successful establishment of a PB/ATRA combination regimen will lead to Phase II trials of this combination in resistant myeloid malignancies for which few effective treatments are currently available.