Combination of YM155, a survivin suppressant, with bendamustine and rituximab: a new combination therapy to treat relapsed/refractory diffuse large B-cell lymphoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.
Authors' Affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
Naoki
N
Kaneko
Keisuke
K
Mitsuoka
Nobuaki
N
Amino
Kentaro
K
Yamanaka
Aya
A
Kita
Masamichi
M
Mori
Sosuke
S
Miyoshi
Sadao
S
Kuromitsu
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D000069283:Rituximab; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
D058846:Antibodies, Monoclonal, Murine-Derived; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D009588:Nitrogen Mustard Compounds; D000077022:Survivin; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; C523798:sepantronium