Bryostatins

General information

Bryostatins are naturally occurring antineoplastic macrocyclic lactones derived from the marine invertebrate Bugula neritina , different varieties being isolated from different populations of the same species. More than 13 structurally related compounds have been isolated [ , ], and there is a variety of synthetic analogues [ ]. The bryostatins modulate the activity of protein kinase C.

Bryostatin 1 binds to the regulatory domain of protein kinase C; short-term exposure promotes activation of protein kinase C, whereas prolonged exposure promotes significant down-regulation [ ]. In preclinical and phase I clinical studies it had promising antitumor and immunomodulating effects. It amplifies expansion of myeloid and erythroid progenitor cells stimulated by the cytokines GM-CSF, M-CSF, and IL-3. Similarly, it induces the production of peripheral blood mononuclear cells with enhanced lymphokine-activated killer cell activity and proliferation in the presence of IL-2 [ ].

In a phase II study, 17 patients with progressive indolent non-Hodgkin’s lymphoma, previously treated with chemotherapy, received bryostatin 1 [ ]. Phlebitis was initially due to the 60% ethanol formulation used for administration, and the subsequent use of another formulation (60% polyethylene glycol, 30% ethanol, 10% Tween 80) reduced the incidence. In one patient, bryostatin 1 was withdrawn because of grade 2 thrombocytopenia. The dose-limiting adverse effect was myalgia, which occurred in eight patients.

Other adverse effects include fatigue, nausea, headache, vomiting, dyspnea, ataxia, anorexia, anemia, and lymphopenia [ ].

In a phase-II study, 14 patients with metastatic cervical cancer or recurrent disease not eligible for surgery or radiation received bryostatin 1 50–65 micrograms/m ² + cisplatin 50 mg/m ² . The most common adverse effects were myalgia, anemia, and nausea or vomiting; one patient had a hypersensitivity reaction and one developed grade 3 nephrotoxicity [ ].