bryostatin-1 and Multiple-Myeloma

Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine.. We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled.. The dose-limiting toxicity was myalgia. The MTD and recommended Phase II dose of bryostatin 1 was 50 microg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting > or =6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h.. Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bryostatins; Female; Flow Cytometry; Humans; Lactones; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Macrolides; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Salvage Therapy; Vincristine

Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, is a protein kinase C (PKC) modulator which has shown both preclinical and clinical activity in lymphoid malignancies. We conducted a phase II trial of bryostatin 1 administered at a dose of 120 microg/m2 by 72-h continuous infusion every 2 weeks in patients with relapsed multiple myeloma. Treatment was well tolerated with myalgias constituting the primaray toxicity. There were no responses in nine evaluable patients. The preclinical anti-lymphoid activity is strong enough to support further exploration of bryostatin 1 in different schedules and in combination therapy for multiple myeloma.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Female; Humans; Lactones; Macrolides; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Treatment Outcome

Interferon-alpha (IFN-alpha) is a pleotropic cytokine that has clinical activity against a wide variety of malignancies, including multiple myeloma (MM). In vitro, IFN-alpha has diverse effects on both normal and malignant cells, however, the exact mechanisms responsible for its clinical anti-tumour activity remain unclear. We found that IFN-alpha inhibited MM cell proliferation in association with cell cycle arrest at G1 and limited the clonogenic growth of both MM cell lines and primary patient specimens. At the doses tested, IFN-alpha was not cytotoxic, but induced terminal plasma cell differentiation resulting in the loss of clonogenicity. These activities were markedly enhanced by the major MM growth factor interleukin 6 (IL-6). Moreover, IL-6 was required for this process, as neutralizing antibodies against IL-6 inhibited the effects of IFN-alpha. IL-6 also induced MM cell terminal differentiation when combined with a second, unrelated, antiproliferative agent bryostatin-1, suggesting that its differentiating activities are preferentially enhanced in the presence of agents that inhibit cell cycling. These results suggest that the differentiating activities of IFN-alpha may play a role in its clinical antimyeloma activity and provide the rationale for clinical differentiation therapy in MM.

Topics: Analysis of Variance; Apoptosis; Bryostatins; Cell Differentiation; Cell Division; Clone Cells; Hematopoietic Stem Cells; Humans; Immune Sera; Interferon-alpha; Interleukin-6; Lactones; Macrolides; Mitogens; Multiple Myeloma; Tumor Cells, Cultured