Significant growth inhibition of orthotopic pancreatic ductal adenocarcinoma by CpG oligonucleotides in immunodeficient mice.
OBJECTIVE
The high rate of local recurrence after radical resection of pancreatic ductal adenocarcinoma fosters intensive efforts to develop new approaches for adjuvant treatment. Antisense and modified oligodeoxynucleotides (ODNs) have demonstrated significant tumour growth inhibitory effects in preclinical systems. Our aim was to evaluate the possible therapeutic potential of ODNs containing unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG motifs).


METHODS
For in vitro analysis, [(3)H]thymidine incorporation for DNA synthesis, colorimetric cell vitality assay (EZ4U assay), and DNA fragmentation assay (JAM-[(3)H]thymidine incorporation assay) to test for apoptosis were performed. In vivo testing was done on an orthotopic pancreatic xenotransplantation model using severe combined immunodeficient (SCID) beige and nude mice.


RESULTS
No significant differential effect of either control ODN or CpG-1826 ODN with regard to tumour cell proliferation or induction of apoptosis was observed in vitro. In vivo, ODN-1826 proved to have a significant inhibitory effect (up to 40% reduction of tumour weight) when compared with tumour-bearing animals treated with saline or control ODN. This was accompanied by sevenfold increase in splenomegaly and moderate hepatomegaly. The reduction of tumour weight by ODN-1826 was only slightly more pronounced in nude compared with SCID beige mice.


CONCLUSIONS
CpG-1826 induces significant growth-inhibitory effects on orthotopic xenotransplanted pancreatic tumours in highly immunodeficient mice, which might be explained by innate immunity mechanisms and possibly a complex interaction of tumour and stroma cells.
Tepel
J
J
Clinic for General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105, Kiel, Germany. jtepel@klinikum.uni-kiel.de
Dagvadorj
O
O
Kapischke
M
M
Sipos
B
B
Leins
A
A
Kremer
B
B
Kalthoff
H
H
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000627:therapeutic use*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D005260:Female; D006529:Hepatomegaly / Q000473:pathology; D016867:Immunocompromised Host; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D013163:Splenomegaly / Q000473:pathology
C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D004247:DNA