title: Biological activity of 26-succinylbryostatin 1.
abstract: Bryostatin 1, a macrocyclic lactone, has undergone phase I trials as an anticancer agent. Because of the lipid solubility of this compound it must be delivered either in ethanol or in a PET formulation. During the trial, these vehicles caused a large number of treatment-related side effects. We have synthesized the triethanolamine salt of 26-succinylbryostatin 1 and find that this compound is approx. 100-fold more water soluble than bryostatin 1. Because of the potential for clinical use, we have evaluated the biologic activity of this compound. We find that in a concentration-dependent manner 26-succinylbryostatin 1 is capable of activating protein kinase C (PKC) in vitro and displacing [3H]PDBu from PKC. However, at all concentrations tested the activity was less than the parent compound bryostatin 1. Addition of bryostatin 1 but not 26-succinylbryostatin 1 to U937 leukemic cells in culture stimulated a drop in cytosolic PKC, secondary to translocation of PKC to the membrane. Although 26-succinylbryostatin 1 did not stimulate a drop in the cytosolic levels of PKC, addition to U937 cells activated transcription from an AP-1 enhancer construct and c-Jun protein phosphorylation in a similar fashion to bryostatin 1 and differentiation of U937 cells. Unlike bryostatin 1, 26-succinylbryostatin 1 was unable to cause aggregation of human platelets. Although injection of bryostatin-1 into mice carrying B16 melanoma inhibits tumor growth, there was no significant inhibition of melanoma growth when identical doses of 26-succinylbryostatin 1 were injected. Therefore, 26-succinylbryostatin 1 shares some but not all of the pharmacologic properities of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.
authors.affiliation: Hawaii Biotechnology Group, Inc., Aiea 96701, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Bignami
authors.forename: F
authors.initials: F
authors.lastname: Wagner
authors.forename: P G
authors.initials: PG
authors.lastname: Grothaus
authors.forename: P
authors.initials: P
authors.lastname: Rustagi
authors.forename: D E
authors.initials: DE
authors.lastname: Davis
authors.forename: A S
authors.initials: AS
authors.lastname: Kraft
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D054713:Bryostatins; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004789:Enzyme Activation; D005982:Glutathione Transferase; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D018942:Macrolides; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C100721:26-succinylbryostatin 1; D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011993:Recombinant Fusion Proteins; D015240:Phorbol 12,13-Dibutyrate; C046785:bryostatin 1; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase; D011493:Protein Kinase C