Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro

Abstract

Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.

Requirement for myeloid growth factors in the differentiation of acute promyelocytic leukaemia

“…ATO is clinically effective in the treatment of APL relapsing after therapy with ATRA and has multiple effects on APL cells including inhibiting cellular growth, inducing apoptosis, and promoting differentiation (Shao et al , 1998; Soignet et al , 1998; Cai et al , 2000; Miller et al , 2002). Bryostatin‐1 is a macrocyclic lactone that acts as a partial agonist of protein kinase C (Berkow & Kraft, 1985; Gschwendt et al , 1988) and has potent antiproliferative (Jones et al , 1990; Grant et al , 1991), cell cycle inhibitory (Matsui et al , 2002; Clark et al , 2004), and differentiating (Stone et al , 1988; Drexler et al , 1989; Matsui et al , 2002) effects on acute myeloid leukaemia cells, including APL (Song & Norman, 1999). Treatment of NB4 (Fig 5A) and clinical APL cells (Fig 6) with ATO or bryostatin‐1 induced phenotypic differentiation as measured by myeloid surface antigen expression, although the differentiation of clinical APL samples with ATO was associated with increased levels of the granulocytic cell surface antigen CD15 rather than CD11b as others have reported (Shao et al , 1998).…”

Bryostatin and CD40‐ligand enhance apoptosis resistance and induce expression of cell survival genes in B‐cell chronic lymphocytic leukaemia

“…Bryostatin-1 has anti-leukaemia activity in vitro against acute myelogenous leukaemias (AMLs) (Jones et al, 1990), and in vivo against CLL xenografts (Mohammad et al, 1998). This PKC modulator has also been reported to down-regulate expression of the anti-apoptotic protein Bcl-2 and to induce differentiation and apoptosis in HL-60 acute promyelomonocytic leukaemia cells (Vrana et al, 1998).…”

Autologous bone marrow transplantation with 4‐hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10‐year experience

“…The remaining cells were incubated with graded concentrations of 4HC (0–60 μg/ml) for 30 min at 37°C. The cells were cultured for CFU‐L (scored on d 3 through d 6) and granulocyte–macrophage colony‐forming units (CFU‐GM) (scored on d 13 or d 14) as previously described (Jones et al , 1990a,b; Miller et al , 1991). The sensitivity of the colonies to 4HC was defined as the estimated slope of the linear regression line formed by plotting the logarithm of the surviving fraction of CFU‐L/CFU‐GM against 4HC concentration (Miller et al , 1991).…”