Ascites regression and survival increase in mice bearing advanced-stage human ovarian carcinomas and repeatedly treated intraperitoneally with CpG-ODN.

Abstract

Tumor cell growth, even in advanced stages of ovarian cancer, is nearly always restricted to the peritoneal cavity; therefore, repeated intraperitoneal injections of oligodeoxynucleotides containing dinucleotides with unmethylated CpG motifs (CpG-ODN) recruiting and activating innate effector cells throughout the abdominal cavity to the tumor site might control tumor cell growth and ascites formation. After a single CpG-ODN treatment, in IGROV-1 ovarian tumor ascites-bearing athymic mice, the number of tumor cells declined rapidly and markedly, and ascites volumes declined shortly after treatment (5 h), increasing thereafter at a slower rate than in controls. When administered every 7 days for 4 weeks, CpG-ODN had only a marginal effect on survival time, whereas administration 5 days/wk for 3 or 4 weeks led to a significantly increased survival time as compared with controls (P<0.005) and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Bio-plex assay of cytokine levels in peritoneal fluid of ascites-bearing mice after CpG-ODN treatment revealed an increase in interleukin (IL)-6, IL-10, IL-12, and interferon-gamma at 24 hours, which returned to control mice levels at 48 to 96 hours, whereas the high levels of angiogenic factors remained unchanged. Depletion of natural killer or monocytes/macrophages only slightly influenced the CpG-ODN-induced reduction of ascites tumor cells, indicating that the antitumor activity might not be related to a specific cell/cytokine but rather to the repertoire of cells and cytokines accumulated in the peritoneal cavity. Thus, our data suggest a relevant role for repeated activation of cells and cytokines of innate immunity in the therapy of ovarian cancer patients with malignant ascites.

• Authors: Michelandrea De Cesare, Lucia Sfondrini, Manuela Campiglio, Michele Sommariva, Francesca Bianchi, Paola Perego, Nico van Rooijen, Rosanna Supino, Cristiano Rumio, Franco Zunino, Graziella Pratesi, Elda Tagliabue, Andrea Balsari
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 33 Issue 1 Pg. 8-15 (Jan 2010) ISSN: 1537-4513 [Electronic] United States
• PMID: 19952960 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• CPG-oligonucleotide
• Oligodeoxyribonucleotides

Topics

• Adjuvants, Immunologic (administration & dosage)
• Animals
• Ascites (drug therapy, etiology)
• Drug Administration Schedule
• Female
• Humans
• Injections, Intraperitoneal
• Mice
• Mice, Nude
• Oligodeoxyribonucleotides (administration & dosage, immunology)
• Ovarian Neoplasms (complications, drug therapy, immunology)
• Xenograft Model Antitumor Assays