Bryostatin-1: a novel PKC inhibitor in clinical development.
Modulation of PKC represents a novel approach to cancer therapy. Bryostatin-1 is a macrocyclic lactone derived from a marine invertebrate that binds to the regulatory domain of protein kinase C. Short-term exposure to bryostatin-1 promotes activation of PKC, whereas prolonged exposure promotes significant downregulation of PKC. In numerous hematological and solid tumor cell lines, bryostatin-1 inhibits proliferation, induces differentiation, and promotes apoptosis. Furthermore, preclinical studies indicate that bryostatin-1 potently enhances the effect of chemotherapy. In many cases, this effect is sequence specific. Bryostatin-1 is currently in phase I and phase II clinical trials. The major toxicities are myalgias, nausea, and vomiting. Although there is minimal single-agent activity, combinations with standard chemotherapy are providing very encouraging results and indicate a new direction in cancer therapy.
Kortmansky
Jeremy
J
Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Schwartz
Gary K
GK
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis; D054713:Bryostatins; D002454:Cell Differentiation; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015536:Down-Regulation; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology*; D018942:Macrolides; D009325:Nausea / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C