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  • Bryostatin Analogs, Protein Kinase C, Tumor Necrosis Factor, Bryostatin Blood Levels
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Comparison of the antitumor activity of bryostatins 1, 5, and 8

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.

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Author information

Correspondence to Andrew S. Kraft.

Additional information

This work was supported by the American Cancer Society Grant DHP-83 (A.S.K.) by the Fannie E. Rippel Foundation, by the Arizona Disease Control Research Commission, by the Robert B. Dalton Endowment Fund, and by CA44344 from the Division of Cancer Treatment (G.R.P.)

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Kraft, A.S., Woodley, S., Pettit, G.R. et al. Comparison of the antitumor activity of bryostatins 1, 5, and 8. Cancer Chemother. Pharmacol. 37, 271–278 (1995). https://doi.org/10.1007/BF00688328

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Key words

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