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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

Hematology-Oncology Section, Department of Medicine and the Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces macrophage-like differentiation of HL60 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 HL60 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 demonstrated 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 HL60 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 normal 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, hematopoiesis is able to proceed both in vitro and in vivo.

¹ Supported by grants AM-15441 and CA-32733 from NIH.

² Junior Faculty Research Fellow of the American Cancer Society. To whom requests for reprints should be addressed, at Cancer Center, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283.

³ Current address: Division of Hematology/Oncology, University Hospital Case Western Reserve School of Medicine, Cleveland, OH 44106.

⁴ Dr. Hoxie is a Special Fellow of the Leukemia Society of America.

Received 11/ 8/85. Revised 3/26/86. Accepted 3/31/86.

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