Bryostatin 1: a potential anti-leukemic agent for chronic myelomonocytic leukemia

Bryostatin 1 is a macrocyclic lactone which activates protein kinase C (PKC), and is able to induce maturation in cells from some cases of acute myelogenous leukemia. This paper reports that bryostatin inhibits the spontaneous in vitro proliferation of chronic myelomonocytic leukemia cells (CMMoL) in semi-solid medium at concentrations between 10(-8) and 10(-10) M. Growth inhibition was equivalent to or greater than that seen with phorbol-12-myristate-13-acetate. Bryostatin acted primarily as a cytotoxic agent, rather than as a cytostatic agent. The spontaneous in vitro proliferation of CMMoL cells is due to autocrine or paracrine secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). Bryostatin 1 actually increased GM-CSF secretion by CMMoL cells while inhibiting their proliferation. Bryostatin 1 also increased tumor necrosis factor alpha (TNF alpha) secretion by CMMoL cells, and in 2/5 cases the cytotoxic effect of bryostatin 1 on fresh CMMoL cells could be substantially reversed by the addition of antibody to TNF alpha to the culture medium. Bryostatin 1 may produce a cytotoxic effect on CMMoL cells in part by increasing the secretion of, or sensitivity to, TNF alpha, and may have therapeutic potential in CMMoL.