Differential Effects of Phorbol Esters on Normal Myeloid Precursors and Leukemic Cells: Basis for Autologous Bone Marrow Reconstitution in Acute Nonlymphocytic Leukemia Using Phorbol Ester-treated Bone Marrow from Patients in Remission1

The phorbol ester 12-CMetradecanoylphorbol-13-acetate (TPA) in duces macrophage-like differentiation of 111 60 cells and cells from patients with acute nonlymphocytic leukemia (ANLL). We assessed the use of TPA as a means of eradicating residual leukemia from remission bone marrow prior to autologous bone marrow reconstitution. A 30-min incubation with TPA led to marked growth arrest in III.60 cells and in cells from most patients with acute myelogenous leukemia and acute myelomonocytic leukemia, whereas cells from most patients with acute promyelocytic leukemia and acute undifferentiated leukemia demonstra ted a lesser degree of growth arrest. Freezing and thawing, a necessary step in autologous reconstitution, had no effect on the cessation of proliferation induced in 111.60 or ANLL cells preincubated with TPA for 30 min. Virtually normal myeloid precursor growth occurred in normal or remission bone marrow cells preincubated with TPA and then frozen and thawed. Based on these observations, two patients with advanced ANLL in remission underwent marrow ablative therapy followed by autologous reconstitution using TPA-treated bone marrow. Limited nor mal hematopoiesis was reestablished in both patients, although they subsequently experienced leukemic relapse. These studies demonstrate that in ANLL cells, TPA stimulates growth arrest; in contrast, hemato poiesis is able to proceed both in vitro and in vivo.