Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells

Sodium phenylacetate (PA) and sodium phenylbutyrate (PB) are aromatic fatty acids that can effect differentiation in a variety of cell lines at doses that may be clinically attainable. We have studied the impact of these two agents on lineage- and differentiation stage-specific antigen expression, proliferation, apoptosis, and clonogenic cell survival in primary cultures of bone marrow samples from patients with myeloid neoplasms at presentation and in remission and from normal volunteers. PB inhibited the proliferation of primary acute myeloid leukemia cells in suspension culture with an ID₅₀ of 6.6 mM, similar to its ED₅₀ in cell lines. At higher doses (≤5 mM), PB also induced apoptosis. PB inhibited clonogenic leukemia cell growth with a median ID₅₀ of less than 2 mM; however, colony-forming units- granulocyte/macrophage from patients with myelodysplasia and normal volunteers were inhibited with a similar ID₅₀. In contrast to PB, its metabolite PA had no significant effect on either acute myeloid leukemia proliferation or apoptosis. Expression of the monocytic marker CD14 was increased in monocytic and myelomonocytic leukemias in response to PB, and to a lesser extent, PA. Surprisingly, both agents appeared to increase expression of the progenitor cell antigen CD34, as well as the DR locus of the human leukocyte antigen. These data indicate that PB, but not its metabolite PA, has significant cytostatic and differentiating activity against primary neoplastic myeloid cells at doses that may be achievable clinically.