Sepantronium bromide (YM155) enhances response of human B-cell non-Hodgkin lymphoma to rituximab.
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.
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Aya
A
Kita
Keisuke
K
Mitsuoka
Naoki
N
Kaneko
Mari
M
Nakata
Kentaro
K
Yamanaka
Makoto
M
Jitsuoka
Sosuke
S
Miyoshi
Akihiro
A
Noda
Masamichi
M
Mori
Takahito
T
Nakahara
Masao
M
Sasamata
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D016393:Lymphoma, B-Cell / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009285:Naphthoquinones / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D000069283:Rituximab; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007093:Imidazoles; D009285:Naphthoquinones; D000069283:Rituximab; C523798:sepantronium