Comparison of the antitumor activity of bryostatins 1, 5, and 8

Andrew S. Kraft, Steven Woodley, George Pettit, Feng Gao, John C. Coll, Fred Wagner

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Bryostatin 1, a macrocyclic natural lactone isolated from a marine Bryozoan, has undergone phase I testing in humans. Side effects of treatment have included muscle pain and joint aches, a transient decrease in platelets, and the release of tumor necrosis factor alpha (TNFα) and IL-6 into the blood stream. In animals, anticancer activity has been demonstrated against murine leukemias, lymphomas, melanomas, and sarcomas. The mechanism of action of this compound depends in part on its ability to activate protein kinase C. To determine the biologic activity and toxicity of other members of the family of bryostatin compounds, we studied the ability of bryostatins 5 and 8 to inhibit the growth of murine melanoma K1735-M2. Bryostatins 1, 5, and 8 induced equivalent inhibition of melanoma growth, but bryostatins 5 and 8 induced less weight loss than bryostatin 1 (P<0.001). Neither the injection of an antimurine TNFα antibody nor an adenovirus, which produces a mutated TNF receptor inhibiting TNFα activity, into mice had any effect on either bryostatin-induced weight loss or melanoma tumor growth inhibition. Using a novel competition assay, the levels of bryostatin in the plasma were measured. The approximate half-life (t1/2) of bryostatin was 8.62 min, the clearance (Cl) 3.53 ml/min and the AUC 322.20 nmol/l min. A similar result was obtained with each bryostatin analog. These results suggest that human testing of additional bryostatin analogs may yield compounds with similar antitumor activity but decreased side effects. A novel assay to measure the level of all bryostatins in the plasma of patients undergoing treatment is described.

Original languageEnglish (US)
Pages (from-to)271-278
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume37
Issue number3
DOIs
StatePublished - May 1995

Keywords

  • Bryostatin analogs
  • Bryostatin blood levels
  • Protein kinase C
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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