sepantronium and Lymphoma--Large-B-Cell--Diffuse

Few effective therapeutic options exist for patients with refractory diffuse large B-cell lymphoma (DLBCL). YM155 is a survivin suppressant with activity against DLBCL in a phase I trial. This phase II study was conducted to better characterize the toxicity and efficacy of this small molecule in patients with refractory DLBCL.. Forty-one patients with a median age of 66 years and 3 prior regimens were enrolled and treated with a YM155 dose of 5 mg/m(2)/d by continuous infusion for 168 hours every 21 days for up to 15 cycles of treatment. The median number of completed cycles was 3.. One patient had a complete remission (CR) (2.4%) with an additional 2 patients (5.9%) responding, with a median progression-free survival of 58 days.. YM155 was well tolerated with major toxicities including anemia and fatigue. Whereas YM155 had limited single-agent activity, preclinical data suggest its role in combination with other agents, including rituximab, and a study of that combination in ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Naphthoquinones; Survivin; Young Adult

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models.. Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts.. The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab.. These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.

Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bendamustine Hydrochloride; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Mice; Naphthoquinones; Neoplasm Recurrence, Local; Nitrogen Mustard Compounds; Rituximab; Survivin; Xenograft Model Antitumor Assays

Survivin and STAT3 pathway have been reported to be important for the growth of diffuse large B-cell lymphoma (DLBCL) cells. Here we investigated the antitumor activity of sepantronium bromide (YM155), a survivin suppressant, in combination with STAT3 inhibitors in DLBCL cell lines in vitro. YM155 synergistically enhanced STAT3 inhibitors (AG490 and STA-21)-induced apoptosis in DLBCL cell lines. Moreover, rituximab, which shows inhibitory activity against STAT3, also sensitized DLBCL cell lines to YM155 regardless of sensitivity to rituximab. These results suggest that combining the inhibition of survivin with STAT3 pathway is an attractive and potentially effective way for the treatment of DLBCL.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Flow Cytometry; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Naphthoquinones; Polycyclic Compounds; STAT3 Transcription Factor; Survivin; Tumor Cells, Cultured; Tyrphostins