COMPARISON OF THE ANTITUMOR-ACTIVITY OF BRYOSTATIN-1, BRYOSTATIN-5, AND BRYOSTATIN-8

Citation
As. Kraft et al., COMPARISON OF THE ANTITUMOR-ACTIVITY OF BRYOSTATIN-1, BRYOSTATIN-5, AND BRYOSTATIN-8, Cancer chemotherapy and pharmacology, 37(3), 1996, pp. 271-278
Citations number
30
Categorie Soggetti
Pharmacology & Pharmacy",Oncology
ISSN journal
03445704
Volume
37
Issue
3
Year of publication
1996
Pages
271 - 278
Database
ISI
SICI code
0344-5704(1996)37:3<271:COTAOB>2.0.ZU;2-C
Abstract
Bryostatin 1, a macrocyclic natural lactone isolated from a marine Bry ozoan, has undergone phase I testing in humans. Side effects of treatm ent have included muscle pain and joint aches, a transient decrease in platelets, and the release of tumor necrosis factor alpha (TNF alpha) and IL-6 into the blood stream. In animals, anticancer activity has b een demonstrated against murine leukemias, lymphomas, melanomas, and s arcomas. The mechanism of action of this compound depends in part on i ts ability to activate protein kinase C. To determine the biologic act ivity and toxicity of other members of the family of bryostatin compou nds, we studied the ability of bryostatins 5 and 8 to inhibit the grow th of murine melanoma K1735-M2. Bryostatins 1, 5, and 8 induced equiva lent inhibition of melanoma growth, but bryostatins 5 and 8 induced le ss weight loss than bryostatin 1 (P < 0.001). Neither the injection of an antimurine TNF alpha antibody nor an adenovirus, which produces a mutated TNF receptor inhibiting TNF alpha activity, into mice had any effect on either bryostatin-induced weight loss or melanoma tumor grow th inhibition. Using a novel competition assay, the levels of bryostat in in the plasma were measured. The approximate half-life (t(1/2)) of bryostatin was 8.62 min, the clearance (Cl) 3.53 ml/min and the AUC 32 2.20 nmol/l min. A similar result was obtained with each bryostatin an alog. These results suggest that human testing of additional bryostati n analogs may yield compounds with similar antitumor activity but decr eased side effects. A novel assay to measure the level of all bryostat ins in the plasma of patients undergoing treatment is described.