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In Vivo Administration of the Anticancer Agent Bryostatin 1 Activates Platelets and Neutrophils and Modulates Protein Kinase C Activity¹

Division of Hematology/Oncology [A. S. K., L. S. P. R.], Division of Pediatric Hematology/Oncology [R. L. B., R. D.] and Department of Pathology [W. H. B.], University of Alabama at Birmingham, Birmingham, Alabama 35294, and Cancer Research Institute and Department of Chemistry, Arizona State University, Tempe, Arizona 85287 [G. R. P.]

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 µg/kg with half-maximal activation occurring at 3 µg/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 bloassay 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.

¹ Supported by CA42533 (A. S. K.), the Fannie E. Rippel Foundation, the Arizona Disease Control Research Commission, the Robert B. Dalton Endowment Fund (G. R. P.), a grant from the American Heart Association (R. L. B.), and NIH Grant AI15986.

² To whom requests for reprints should be addressed.

Received 11/24/92. Accepted 4/ 9/93.

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