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 (TNF alpha) 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 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 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.

The promise of molecular targeted therapies: Protein kinase inhibitors in the treatment of cutaneous malignancies

“…60 Although the mechanism is unclear, the PKC inhibitor bryostatin 1 has antitumor effects on murine melanoma cell lines. [61][62][63] Although one phase I trial showed early responses to bryostatin 1, 64 other phase I/II trials have not resulted in a favorable response. [65][66][67][68] In a phase I study, the PKC and 3-phosphoinositide-dependent protein kinase-1 inhibitor UNC-01 has shown a partial response in one patient with melanoma.…”

Evidence for the Biosynthesis of Bryostatins by the Bacterial Symbiont “ Candidatus Endobugula sertula” of the Bryozoan Bugula neritina

“…Bryostatin 1 also shows promise for treatment of ovarian and breast cancers and for enhancing lymphocyte survival during radiation treatment (3,4,5,12,13,16,20,21,28,32,33). Other bryostatins may prove to be valuable therapeutic agents as well (19). Research and development of the bryostatins are currently severely limited by inadequate availability of these compounds.…”

Bryostatin-5 Blocks Stromal Cell–Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors

“…Of the >20 known bryostatins, bryostatin-1 is the best characterized. Bryostatin-1 potently inhibits tumor growth, metastasis, and angiogenesis in vitro and in vivo (16)(17)(18), and it is currently being evaluated in clinical studies for its therapeutic potential against various types of cancer (19,20). A variety of studies have been performed to better understand the molecular mechanisms of tumor suppression induced by bryostatin-1 (21,22,38).…”

“…Currently, >20 natural bryostatins are known. Bryostatin-1 is the most well studied, as it possesses a unique pharmacologic profile as a cancer chemotherapeutic agent and inhibits tumor growth, metastasis, and angiogenesis in vitro and in vivo (16)(17)(18). Bryostatin-1 is currently being evaluated alone and in combination with other chemotherapeutic agents in >40 clinical trials for numerous cancer types, including melanoma, myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, AIDS-related lymphoma, breast cancer, and non-small cell lung cancers (19,20).…”

“…S2A). It inhibits the growth of murine melanoma K1735-M2 similar to bryostatin-1 but with fewer side effects in animal experiments (17). Thus far, no study has addressed the involvement of bryostatins in SDF-1/CXCR4 signaling processes.…”