Sepantronium bromide (YM155) enhances response of human B-cell non-Hodgkin lymphoma to rituximab.

J Pharmacol Exp Ther. 2012 Oct;343(1):178-83.

Kita A, Mitsuoka K, Kaneko N, Nakata M, Yamanaka K, Jitsuoka M, Miyoshi S, Noda A, Mori M, Nakahara T, Sasamata M.

Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.

 

Abstract

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′-(18)F-fluoro-D-glucose ((18)F-FDG) and 3′-(18)F-fluoro-3′-deoxythymidine ((18)F-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 (18)F-FDG and (18)F-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 (18)F-FLT and (18)F-FDG PET imaging may allow the early functional evaluation of treatment responses in patients with B-NHL.

PMID: 22787117

 

Supplement:

Mitsuoka Keisuke-1

(A) YM155 Enhances Antitumor Activity of Rituximab against Subcutaneous Xenograft Tumors.

Combination treatment with YM155 and rituximab resulted in significant tumor regression (>100% inhibition) in WSU-DLCL-2 xenografts of BALB/c nude mice. YM155 was given as a 7-day continuous subcutaneous infusion starting on day 0, and rituximab was administered intravenously by bolus injection on days 0 and 2. Tumor volume on day 21 was compared between each single-treatment group and the combination group by using Student’s t test. *, P < 0.05 versus YM155 monotherapy group. ###, P < 0.001 versus rituximab monotherapy group. Mean, S.E.M. (n = 5 mice/group).

(B) PET imaging identifies early metabolic changes after chemotherapy treatment. Representative images of 18F-FDG and 18F-FLT in WSU-DLCL-2 xenograft-bearing mice on days 0 and 3 of treatment are shown. Within 3 days of treatment, a decrease (−42%) in 18F-FDG uptake was achieved in the combination treatment group (P < 0.05 versus control). Combination treatment significantly reduced the tumor uptake of 18F-FLT by −39% (P < 0.01 versus control). Arrows indicate the WSU-DLCL-2 xenograft.

 

 

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