Development of immunomodulatory six base-length non-CpG motif oligonucleotides for cancer vaccination.
We have previously described a novel family of immunomodulatory synthetic oligonucleotides characterized by a phosphodiester backbone, a length of six bases and a 5'G3xG23' sequence, where x is A, C, G or T. In the present study, we have evaluated whether these 5'G3xG23' oligonucleotides possess additional activities essential for adequate cancer vaccination. Immunization for the treatment of cancer requires an adjuvant, a source of tumor-associated antigen(s), for example apoptotic cancer cells, and a way to overcome the escape of tumor cells from the immune system, for example the up-regulation of Fas ligand (FasL) on the surface of cancer cells. The results show that phosphodiester 5'G3AG23' and 5'G3TG23' oligonucleotides have a direct activity on a number of different cancer cells by inducing apoptosis (release of cytochrome C, activation of caspase-3, cleavage of poly [ADP-ribose] polymerase, degradation of nuclear mitotic apparatus protein and translocation of phophatidylserine at the cell surface). In addition, the 5'G3AG23', 5'G3CG23', and 5'G3TG23' oligonucleotides were found to down-regulate the levels of FasL on the surface of cancer cells. These immunomodulatory phosphodiester six base-length oligonucleotides, which are capable of inducing apoptosis in cancer cells as well as downregulating the expression of FasL at their cell surface, may have application as cancer cell vaccines.
Filion
Mario C
MC
Bioniche Therapeutics Division, Bioniche Life Sciences, 6100 Royalmount Avenue, Montréal, Que., Canada, H4P 2R2. mario.filion@bioniche.com
Filion
Benoit
B
Roy
Julie
J
Ménard
Sonia
S
Reader
Stéphanie
S
Phillips
Nigel C
NC
D000276:Adjuvants, Immunologic; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009841:Oligonucleotides; D019014:fas Receptor