Antitumor effect of G3139 Bcl-2 antisense oligonucleotide is independent of its immune stimulation by CpG motifs in SCID mice.
The Bcl-2 antisense oligonucleotide (AS-ODN) G3139 chemosensitizes human malignancies by downregulating the antiapoptotic protein Bcl-2. Because G3139 contains two potential immunostimulatory CpG motifs, we asked if immune stimulation contributes to the antitumor activity observed previously. 5'-Methylation of cytosines in CpG motifs abrogates immune stimulation by oligonucleotides. We, therefore, studied the antitumor and immunostimulatory potential of G3139 vs. an identical oligonucleotide, except for methylation of cytosines in the two CpG motifs (G4232). In a human melanoma SCID mouse xenotransplantation model, G3139 or G4232 was administered by continuous subcutaneous (s.c.) or bolus intraperitoneal (i.p.) infusion. Both G3139 and G4232 significantly reduced tumor growth by about one third relative to the saline-treated group. Furthermore, we noted a similar downregulation of Bcl-2 expression and increase in tumor cell apoptosis caused by G3139 and G4232 compared with saline controls. However, mice treated with G3139 had a pronounced increase in spleen weight and interleukin-12 (IL-12) plasma levels relative to mice treated with either G4232 or saline. Splenomegaly and elevated IL-12 plasma levels suggest that G3139 can be immunostimulatory. However, there is clear evidence that the antitumor effect of G3139 in this model appears to be a Bcl-2 antisense effect that is independent of immune stimulation, as G3139 and its immune-silent counterpart G4232 caused similar tumor suppression and apoptosis induction.
Wacheck
Volker
V
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, A-1090 Vienna, Austria. Volker.Wacheck@univie.ac.at
Krepler
Clemens
C
Strommer
Sabine
S
Heere-Ress
Elisabeth
E
Klem
Robert
R
Pehamberger
Hubert
H
Eichler
Hans-Georg
HG
Jansen
Burkhard
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D013873:Thionucleotides / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D015850:Interleukin-6; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D018664:Interleukin-12; C408162:oblimersen