Ascites regression and survival increase in mice bearing advanced-stage human ovarian carcinomas and repeatedly treated intraperitoneally with CpG-ODN.
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.
De Cesare
Michelandrea
M
Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Università degli Studi di Milano, 20133 Milan, Italy.
Sfondrini
Lucia
L
Campiglio
Manuela
M
Sommariva
Michele
M
Bianchi
Francesca
F
Perego
Paola
P
van Rooijen
Nico
N
Supino
Rosanna
R
Rumio
Cristiano
C
Zunino
Franco
F
Pratesi
Graziella
G
Tagliabue
Elda
E
Balsari
Andrea
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D001201:Ascites / Q000188:drug therapy* / Q000209:etiology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides