Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma.
Survivin is a member of the inhibitor of apoptosis protein (IAP) family and functions both as an apoptosis inhibitor and a regulator of cell division. Survivin overexpression is common in many human tumors and correlates with survival in large cell non-Hodgkin's lymphoma. To evaluate this molecule as a potential therapeutic target in large-cell lymphoma, we evaluated the effect of survivin inhibition both in vitro and in vivo. Using an antisense oligonucleotide (ASO) approach, cell growth was significantly inhibited in the DoHH2, RL and HT lymphoma cell lines. In a lymphoma xenograft model, the development of tumors as well as the growth of established tumors was inhibited in the survivin ASO-treated mice compared to controls. To assess the efficacy of the survivin ASO in combination with other biological agents, we combined the survivin ASO with an anti-CD20 monoclonal antibody, rituximab. The effect of survivin ASO and rituximab in combination was additive in vitro. In vivo, however, suppression of tumor growth with the combination was not significantly superior to controls. We conclude that inhibition of survivin expression is an attractive therapeutic strategy in aggressive non-Hodgkin's lymphomas, and that combining survivin ASO with rituximab may enhance the efficacy of this approach.
Ansell
S M
SM
Division of Hematology, Mayo Clinic, Rochester, MN, USA. ansell.stephen@mayo.edu
Arendt
B K
BK
Grote
D M
DM
Jelinek
D F
DF
Novak
A J
AJ
Wellik
L E
LE
Remstein
E D
ED
Bennett
C F
CF
Fielding
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000077022:Survivin; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D000077022:Survivin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases