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 impac t of these two agents on lineage-and differentiation stage-specific an tigen expression, proliferation, apoptosis, and clonogenic cell surviv al in primary cultures of bone marrow samples from patients with myelo id neoplasms at presentation and in remission and from normal voluntee rs, PB inhibited the proliferation of primary acute myeloid leukemia c ells in suspension culture with an ID50 of 6.6 mM, similar to its ED50 in cell lines, At higher doses (greater than or equal to 5 mm), PB al so induced apoptosis, PB inhibited clonogenic leukemia cell growth wit h a median ID50 of less than 2 mm; however, colony-forming units-granu locyte/macrophage from patients with myelodysplasia and normal volunte ers were inhibited with a similar ID50, In contrast to PB, its metabol ite PA had no significant effect on either acute myeloid leukemia prol iferation or apoptosis, Expression of the monocytic marker CD14 was in creased in monocytic and myelomonocytic leukemias in response to PB, a nd to a lesser extent, PA, Surprisingly, both agents appeared to incre ase 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 b e achievable clinically.