plitidepsin and Lymphoma--Large-B-Cell--Diffuse

Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab. All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations, while rituximab sensitivity varied among different cell lines. Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs. The two agents exhibited synergism at all tested concentrations. For in vivo studies, irradiated athymic nude mice were engrafted with the Ramos lymphoma. Treatment was initiated when the tumors were ~0.5 cm in diameter, and toxic and therapeutic effects were monitored. In the in vivo study, additive effects of the combined two drugs, was demonstrated without an increase in host toxicity. The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas.

Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Female; Humans; Immunophenotyping; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Nude; Peptides, Cyclic; Rituximab; Xenograft Model Antitumor Assays

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Line, Tumor; Cytarabine; Depsipeptides; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; K562 Cells; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, Large B-Cell, Diffuse; Methylprednisolone; Mice; Mice, SCID; Mitochondria; Mitoxantrone; Oxidative Stress; Peptides, Cyclic; Specific Pathogen-Free Organisms; Xenograft Model Antitumor Assays