A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Abstract

Summary Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1-9) intravenous infusions of 25 µg/m 2 bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis.

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma

“…Inhibitors of PKC are being used in clinical trials of patients with relapsed or progressive non-Hodgkin's lymphoma. [55][56][57] If our findings are confirmed, the addition of PKC inhibitors to initial chemotherapy regimens should be considered in clinical trials of this group of patients with DLBCL. As additional immunohistochemical markers of aggressive disease are identified through gene expression studies, our findings suggest that cyclin D2 and PKC-b should be included with these new markers to form a 'biological prognostic index' that could be used in clinical trials to stratify patients for risk-adjusted therapies.…”

T-cell non-Hodgkin lymphoma

“…127 Protein kinase C-modulating agents UCN-01 and bryostatin are also being studied. 128,129 Furthermore, histone deacetylase (HDAC) inhibitors (such as depsipeptide and SAHA) increase histone acetylation leading to cellular differentiation, decreased cell proliferation, and induction of cell death and are being examined in patients with T-cell NHL. 130 The role of viral pathogenesis in T-cell NHL tumor development continues to be studied as a potential target of drug therapy.…”

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

“…In several murine and human tumor models, this agent displayed antitumor, and in some cases, differentiationinducing activity also, and is now undergoing early clinical evaluation. In these studies, myalgia appeared to be the doselimiting toxicity, and a few partial responses were documented in patients suffering from refractory malignant melanoma, non-Hodgkin's lymphoma, or ovarian carcinoma [85][86][87][88].…”