The antineoplastic agent bryostatin-1 (Bryo-1) potently activates human monocytes to produce cytokines. Synergy with interleukin-2 (IL-2)

Bryo-1 is a ligand and modulator of protein kinase C (PKC) that has attracted considerable interest because of its potent in vitro and in vivo antitumor activity. The potential clinical use of bryo-1 as an antineoplastic agent is currently being evaluated and promising effects against metastatic malignant melanoma were recently reported. Although the exact mechanisms responsible for its antitumor activity is not clear, numerous studies have shown that bryo-1 can exert direct cytotoxic effects on tumor cells. However, bryo-1 may also inhibit tumor growth in vivo by indirect mechanisms, related to its ability to stimulate host immune responses. Monocytes represent a main recognition system for foreign cells, including tumor cells; play a major role in antigen presentation; and are an important source of a wide repertoire of products endowed with antitumor and immunomodulatory properties, including the cytokines interleukin-1 (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF-alpha). The present study was designed to investigate the effects of bryo-1 on the activation of human monocytes and to analyze its possible interaction with IL-2. Stimulation of monocytes with subnanomolar concentrations of bryo-1 significantly upregulated the constitutive levels of IL-8 mRNA and induced the expression of IL-1beta, TNF-alpha, and IL-6 mRNA in a time and dose-dependent manner. Accordingly, secretion of all four cytokines was induced by bryo-1. Furthermore, we showed that bryo-1 selectively synergized with IL-2 in triggering monocyte activation, and this effect seemed to be dependent, at least in part, on the ability of bryo-1 to upregulate IL-2 receptor gamma chain expression. These results show for the first time that bryo-1 is a powerful activator of human monocytes, and suggest that stimulation of monokine secretion by bryo-1 may represent at least one of the mechanisms responsible for the in vivo antitumor activity of this drug. Finally, the fact that bryo-1 synergizes with IL-2 in triggering monocyte activation makes this compound an interesting candidate for clinical trials in combination with IL-2. (C) American Society of Clinical Oncology 1997

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