) Bryostatin 1(bryo 1) is a mycrocylic lactone derived from the marine bryozoa Bugula neritina. It possesses several biological and antitumor properties in preclinical models and has recently entered clinical trials in cancer patients. The objectives of this project are to: 1) Determine the efficacy of bryo 1 in patients with relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) when given at maximum tolerated dose (MTD) by continuous intravenous infusion (CIVI) over 72 h; 2) Determine the MTD of vincristine (VCR), when given by i.v. bolus at the end of each bryo 1 infusion; and 3) Conduct specific laboratory correlative studies on tumor specimens of study subjects related to induction of B cell differentiation and apoptosis. Based on 2-stage study design, it is estimated that 45 patients will be entered on this phase II study at Wayne State University, Henry Ford Hospital and the VA Medical Center of Detroit, in a consortium arrangement. Eligible patients will receive bryo 1 by CIVI over 72 h every two weeks and re-evaluated after 4 treatments. Those with stable disease, partial or complete remission will continue on therapy. Patients with progressive disease will receive bryo 1 CIVI followed by escalating doses of VCR and evaluated for toxicity and response. Tumor-bearing tissues (blood, bone marrow or lymph nodes) will be analyzed by flow cytometry for apoptosis and phenotypic markers before and during treatment. Apoptosis will be evaluated using DNA fluorescence with propidium iodide and 7-amino actinomycin D. A 3-color immunofluorescence staining of surface antigens with monoclonal antibodies will be used for detection of changes in surface phenotypes of malignant cells. This study represents a novel approach to the treatment of NHL and CLL patients where an estimated number of 63,7000 cases will be diagnosed in the U.S. in 1996; more than half will die of their disease.
