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

Roger L. Berkow, Larry Schlabach, Robert Dodson, William H. Benjamin, George R. Pettit, Pradip Rustagi, Andrew S. Kraft

Research output: Contribution to journalArticle

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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 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 bioassay dem-onstrated 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.

Original languageEnglish (US)
Pages (from-to)2810-2815
Number of pages6
JournalCancer Research
Volume53
Issue number12
StatePublished - Jun 15 1993

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Antineoplastic Agents
Protein Kinase C
Neutrophils
Blood Platelets
Biological Assay
bryostatin 1
Lymphoma
Neutrophil Activation
B-Cell Lymphoma
Lactones
Melanoma
Leukemia
Spleen
Cell Culture Techniques
Injections
Membranes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Berkow, R. L., Schlabach, L., Dodson, R., Benjamin, W. H., Pettit, G. R., Rustagi, P., & Kraft, A. S. (1993). In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. Cancer Research, 53(12), 2810-2815.

In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. / Berkow, Roger L.; Schlabach, Larry; Dodson, Robert; Benjamin, William H.; Pettit, George R.; Rustagi, Pradip; Kraft, Andrew S.

In: Cancer Research, Vol. 53, No. 12, 15.06.1993, p. 2810-2815.

Research output: Contribution to journalArticle

Berkow, RL, Schlabach, L, Dodson, R, Benjamin, WH, Pettit, GR, Rustagi, P & Kraft, AS 1993, 'In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity', Cancer Research, vol. 53, no. 12, pp. 2810-2815.
Berkow, Roger L. ; Schlabach, Larry ; Dodson, Robert ; Benjamin, William H. ; Pettit, George R. ; Rustagi, Pradip ; Kraft, Andrew S. / In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. In: Cancer Research. 1993 ; Vol. 53, No. 12. pp. 2810-2815.
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