In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity.

Academic Article

Abstract

  • Bryostatin 1 is a naturally occurring macrocyclic lactone which when applied to cells in culture activates protein kinase C (PKC). In vivo bryostatin 1 functions as an anticancer agent with activity against murine lymphomas, leukemias, and melanoma. Because all organs and tissues contain PKC, normal cells would also be a likely target for this agent. Here we demonstrate that in vivo administration of bryostatin 1 activates platelets over a dose range of 0.4 to 40 micrograms/kg with half-maximal activation occurring at 3 micrograms/kg and stimulation of neutrophils over a similar dose range. This in vivo activation of neutrophils is associated with a rapid decrease in measurable cytosolic PKC, a finding consistent with translocation of the enzyme to the membrane. In contrast, no statistically significant change in PKC location was found in liver, spleen, brain, or L10A B-cell lymphoma. However, in culture the L10A lymphoma did respond to bryostatin 1 with translocation of PKC. To evaluate whether the lack of effect of bryostatin 1 on PKC in organs was secondary to rapid degradation, we developed a bioassay to measure the levels of bryostatin 1 in the blood. To measure the presence of bryostatin 1, human neutrophils were incubated with plasma from mice given injections of different concentrations of bryostatin 1. Using this assay, bryostatin 1 at levels as low as 60 nM could be measured in the plasma. A time course with this bioassay demonstrated that less than 10% of the bryostatin 1 injected was detectable after 2.5 min. These results demonstrate that bryostatin 1 is capable of activating platelets and neutrophils and modulating PKC in vivo. The lack of effect of bryostatin 1 on specific organs may be secondary to the rapid clearance/degradation of this compound from the blood.
  • Keywords

  • Animals, Antineoplastic Agents, Blood Platelets, Bryostatins, Enzyme Activation, Injections, Intravenous, Lactones, Lymphoma, B-Cell, Macrolides, Mice, Mice, Inbred C57BL, Neutrophils, Platelet Activation, Protein Kinase C, Respiratory Burst
  • Author List

  • Berkow RL; Schlabach L; Dodson R; Benjamin WH; Pettit GR; Rustagi P; Kraft AS
  • Start Page

  • 2810
  • End Page

  • 2815
  • Volume

  • 53
  • Issue

  • 12