BRYOSTATIN 1 &VINCRISTINE IN B CELL MALIGNANCIES

Case Western Reserve University, Cleveland OH

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Abstract

Bryostatin 1 is a natural product of the marine invertebrate Bugula neritina of the phylum Ectoprocta. It is the prototype of a 20-member family of macrocyclic lactones, the principal cellular effect of which is activation of protein kinase C11. Bryostatin 1 has a number of antitumor cell effects, including the induction of differentiation of leukemia and lymphoma cell lines and in vitro anti-tumor activity against lung, breast and renal cell carcinoma, melanoma and ovarian sarcoma as well as lymphoma and leukemia cell lines. Most of the cell lineages which respond to bryostatin 1 in vitro also respond in vivo, and bryostatin 1 is also active in xenografts bearing drug-resistant P388 leukemia. Bryostatin 1 enhances neutrophil phagocytic function and activates tumor antigen-stimulated T cells, which can then induce tumor regression following adoptive transfer. The combination of bryostatin 1 with cytotoxic drugs increases or restores drug sensitivity. The objectives of this trial are: 1) To determine the maximum tolerated dose of bryostatin 1 as a 24 hour infusion and vincristine when administered sequentially. 2) To determine the effect of this combination on programmed cell death (apoptosis) 3) To determine the immunomodulatory effect of bryostatin 1. 4) To observe patients for clinical antitumor response after giving combination bryostatin 1 and vincristine.