YM155, a Novel Survivin Suppressant, Improves the Antitumor Effect of Rituximab and Rituximab-Containing Regimens in Diffuse Large B Cell Lymphoma (DLBCL) Xenograft Mouse Models.

Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in many tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive novel target for cancer therapy. YM155 is a novel, small molecule survivin suppressant (Nakahara et al., Cancer Research. 2007;67:8014–21). In this study, we evaluated the antitumor activity of YM155 alone and in combination with rituximab, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), or [rituximab + cytarabin + cisplatin] in DLBCL xenograft models.

Antiproliferative effect of YM155 in a panel of human DLBCL cell lines (DB, Pfeiffer, SU-DHL5, SU-DHL8, WSU-DLCL-2, and RL) was evaluated by sulforhodamine B assay. In in vivo studies, WSU-DLCL-2 and DB were subcutaneously implanted into male BALB/c nu/nu mice. When tumors reached a volume of 300 to 600 mm³, YM155 was administered as a 7-day continuous sc infusion, and the other drugs were administered via iv bolus. Dose and schedule of each drug were adjusted to clinical equivalent dose. PET imaging studies were performed using a Inveon PET/CT system (Siemens Medical Solusion). WSU-DLCL-2 xenografted mice were intravenously injected with [¹⁸F] FLT, and five-minute static PET scans were accqiured at 1h after injection. For each small-animal PET scan, region of interest was drawn over each tumor and over normal tissue on decay-corrected whole-body sagittal imagies.

In in vitro proliferation assays, YM155 showed potent antiproliferative activity against all six DLBCL cell lines, with GI₅₀ values of 0.35 to 3.9 nM. In in vivo studies using WSU-DLCL2 xenograft model, YM155 at 1 and 3 mg/kg induced tumor regression without body weight loss. In combination studies using WSU-DLCL2 xenograft model, YM155 2 mg/kg enhanced antitumor effects of rituximab, R-ICE and [rituximab + cytarabin + cisplatin] without enhancement of the body weight loss. Tumor regression in the combination groups was sustained longer than single treatment groups, and even complete regressions were achievable. Moreover, combination of YM155 1 mg/kg and rituximab induced strong tumor regression in the DB xenograft model, while single-agent treatments did not show significant antitumor effect compared to vehicle control. In [18F]FLT-PET imaging, a significant reduction of FLT uptake in tumor was observed in rituximab combination group, which was more sensitive than the reduction in tumor volume.

YM155 improves the antitumor effect of rituximab and rituximab-containing regimens in diffuse large B cell lymphoma (DLBCL) xenograft mouse models.

Nakata:Astellas Pharma Inc.: Employment. Nakahara:Astellas Pharma Inc.: Employment. Kita:Astellas Pharma Inc.: Employment. Mitsuoka:Astellas Pharma Inc.: Employment. Yamanaka:Astellas Pharma Inc.: Employment. Kaneko:Astellas Pharma Inc.: Employment. Miyoshi:Astellas Pharma Inc.: Employment. Mori:Astellas Pharma Inc.: Employment. Koutoku:Astellas Pharma Inc.: Employment. Sasamata:Astellas Pharma Inc.: Employment.