PT  - JOURNAL ARTICLE
AU  - Aya Kita
AU  - Keisuke Mitsuoka
AU  - Naoki Kaneko
AU  - Mari Nakata
AU  - Kentaro Yamanaka
AU  - Makoto Jitsuoka
AU  - Sosuke Miyoshi
AU  - Akihiro Noda
AU  - Masamichi Mori
AU  - Takahito Nakahara
AU  - Masao Sasamata
TI  - Sepantronium Bromide (YM155) Enhances Response of Human B-Cell Non-Hodgkin Lymphoma to Rituximab
AID  - 10.1124/jpet.112.195925
DP  - 2012 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 178--183
VI  - 343
IP  - 1
4099  - http://jpet.aspetjournals.org/content/343/1/178.short
4100  - http://jpet.aspetjournals.org/content/343/1/178.full
SO  - J Pharmacol Exp Ther2012 Oct 01; 343
AB  - In the treatment of B-cell non-Hodgkin lymphoma (B-NHL) rituximab improves long-term survival in combination with conventional chemotherapy. However, because the majority of patients with B-NHL eventually relapse, the development of more effective therapies is needed. Here, we evaluated the antitumor effects of a combination treatment involving sepantronium bromide (YM155), a first-in-class survivin suppressant, and rituximab in B-NHL xenograft mice models. To determine the efficacy of the combination treatment, YM155- and rituximab-treated B-NHL cell xenografted mice were monitored for tumor size and survival and subjected to 2′-deoxy-2′-18F-fluoro-d-glucose (18F-FDG) and 3′-18F-fluoro-3′-deoxythymidine (18F-FLT) positron emission tomography (PET) imaging. In addition, the cell proliferation status of excised tumors was examined by Ki-67 immunohistochemistry. In DB, WSU-DLCL-2, and Mino xenograft-bearing mice, the combination treatment of YM155 and rituximab induced significant tumor growth inhibition and tumor regression compared with either single agent. On day 3 after the initiation of treatment a significant decrease in both 18F-FDG and 18F-FLT tumor uptake from pretreatment levels was observed in combination treatment groups. The Ki-67 proliferation index was significantly decreased on day 3 in the xenograft models treated with combination treatment, suggesting that the combination of YM155 and rituximab reduced cell proliferation and glucose metabolism. Furthermore, compared with monotherapy, combination treatment prolonged survival times of severe combined immunodeficient mice with disseminated WSU-FSCCL and Jeko B-NHL tumors. Our findings demonstrate that YM155 and rituximab combination treatment enhances antitumor activity in B-NHL xenografts, and 18F-FLT and 18F-FDG PET imaging may allow the early functional evaluation of treatment responses in patients with B-NHL.