title: The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-βII depletion.
abstract: BACKGROUND
  In spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1.
  
  
  METHODS
  Primary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1.
  
  
  RESULTS
  We demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-βII protein. Depletion of protein kinase C-βII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis.
  
  
  CONCLUSIONS
  Our data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low- and high-grade B-cell lymphoma.
authors.affiliation: Department of Medicine III, Hematology and Oncology, Technical University, Munich, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Biberacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Madlen
authors.initials: M
authors.lastname: Oelsner
authors.forename: Michaela
authors.initials: M
authors.lastname: Wagner
authors.forename: Christian
authors.initials: C
authors.lastname: Bogner
authors.forename: Burkhard
authors.initials: B
authors.lastname: Schmidt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer Zum Büschenfelde
authors.forename: Ingo
authors.initials: I
authors.lastname: Ringshausen
mesh_terms: D000906:Antibodies / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D054713:Bryostatins / Q000494:pharmacology*; D004768:Enterotoxins / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D054713:Bryostatins; D004768:Enterotoxins; D000922:Immunotoxins; C431326:RFB4(dsFv)-PE38 recombinant immunotoxin; D051918:Sialic Acid Binding Ig-like Lectin 2; C046785:bryostatin 1; D011493:Protein Kinase C; D064546:Protein Kinase C beta