Varied differentiation responses of human leukemias to bryostatin 1

Bryostatin 1, a macrocyclic lactone isolated from a marine bryozoan, has significant antineoplastic activity against the murine cell line P388. Like phorbol esters, bryostatin 1 is capable of binding to and activating protein kinase C, but these two compounds differ in the ability of bryostatin 1 to act as a tumor promoter. We have investigated whether bryostatin 1 can modulate the differentiated phenotype of fresh samples of human myeloid leukemia. We find that six of seven samples responded to bryostatin treatment with changes associated with a more differentiated phenotype including increases in macrophage-like morphology and an increase in adherence and OKM1 and alpha-naphthyl acetate esterase activity positivity. The percentage of cells within each sample evidencing these changes varied markedly among the seven patients' cells examined. Because of the effects of bryostatin on fresh samples we examined the ability of bryostatin to differentiate four HL-60 cell sublines obtained from different laboratories. We found that two of the cell lines did not respond either with an inhibition of growth or morphological change, while one was inhibited, and one showed both growth inhibition and some induction of macrophage-like morphology when treated with bryostatin. To test whether other differentiating agents would enhance the effects of bryostatin 1, we added tumor necrosis factor alpha and bryostatin to these four cell lines. The addition of both agents effected an additive inhibition of growth. These data suggest that bryostatin 1 alone or in combination with other biological response modifiers may have a role in the treatment of human leukemia.