{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/150068"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/150068","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"LOCOREGIONAL DELIVERY OF UNMETHYLATED CPG-OLIGODEOXYNUCLEOTIDES TO CANCER THERAPY: PRECLINICAL STUDIES","abstract":"Tumor cell growth, even in advanced stages of ovarian cancer, is nearly always restricted to the peritoneal cavity, therefore repeated intraperitoneal injections of 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/week for 3 or 4 weeks led to a significantly increased survival-time as compared to controls and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Depletion of NK 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. However, daily i.p. administration of CpG-ODN induced a significant increase of survival-time but no cure of a single mouse, therefore we screened the effectiveness of CpG-ODN in combination with different agents, including bevacizumab, Poly(I):Poly(C) and cisplatin. Our data indicate that the combination of repeated i.p. CpG-ODN treatments plus bevacizumab and Poly(I):Poly(C) do not significantly increase median survival time, while the association of CpG-ODN and cisplatin revealed a significant increase in mice lifespan. Based on these results, we performed several experments in order to gain inside the molecular mechanisms by which CpG-ODN improves the therapeutic efficacy of cisplatin, a DNA-damaging drug. We demonstrate that an immunostimulatory Toll-like receptor-9 (TLR9) agonist CpG-oligodeoxynucleotide (CpG-ODN) oppositely modulates expression of DNA repair genes in tumor and immune cells. Analyses in silico and in a human ovarian tumor model by microarray revealed downregulation of these genes in tumors and upregulation in immune cells, with no detectable modulation in normal non-immune tissue. CpG-ODN induced activation of cells present in the tumor microenvironment was critical in inducing DNA-repair gene modulation in tumors. In conclusion, the combination of cisplatin with CpG-ODN was effective and well tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to down-modulate DNA repair genes in tumor cell.","abstract_html":"Tumor cell growth, even in advanced stages of ovarian cancer, is nearly always restricted to the peritoneal cavity, therefore repeated intraperitoneal injections of 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/week for 3 or 4 weeks led to a significantly increased survival-time as compared to controls and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Depletion of NK 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. However, daily i.p. administration of CpG-ODN induced a significant increase of survival-time but no cure of a single mouse, therefore we screened the effectiveness of CpG-ODN in combination with different agents, including bevacizumab, Poly(I):Poly(C) and cisplatin. Our data indicate that the combination of repeated i.p. CpG-ODN treatments plus bevacizumab and Poly(I):Poly(C) do not significantly increase median survival time, while the association of CpG-ODN and cisplatin revealed a significant increase in mice lifespan. Based on these results, we performed several experments in order to gain inside the molecular mechanisms by which CpG-ODN improves the therapeutic efficacy of cisplatin, a DNA-damaging drug. We demonstrate that an immunostimulatory Toll-like receptor-9 (TLR9) agonist CpG-oligodeoxynucleotide (CpG-ODN) oppositely modulates expression of DNA repair genes in tumor and immune cells. Analyses in silico and in a human ovarian tumor model by microarray revealed downregulation of these genes in tumors and upregulation in immune cells, with no detectable modulation in normal non-immune tissue. CpG-ODN induced activation of cells present in the tumor microenvironment was critical in inducing DNA-repair gene modulation in tumors. In conclusion, the combination of cisplatin with CpG-ODN was effective and well tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to down-modulate DNA repair genes in tumor cell.","abstract_has_math":false,"creators":["M. Sommariva"],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["tutor: Cristiano Rumio ; coordinatore: Magda Enrica Gioia","RUMIO, CRISTIANO","GIOIA, MAGDA ENRICA"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-12-20","date_published":"2010-12-20","updated_at":"2026-07-27T20:19:15Z","subjects":["IMMUNOTHERAPY","TOLL-LIKE RECEPTOR","CpG-ODN","OVARIAN CANCER","ASCITES","DNA REPAIR","Settore BIO/16 - Anatomia Umana","Settore BIO/17 - Istologia"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["10.13130/sommariva-michele_phd2010-12-20"],"render_values":[{"text":"10.13130/sommariva-michele_phd2010-12-20","href":"https://doi.org/10.13130/sommariva-michele_phd2010-12-20","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2434/150068","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["tutor: Cristiano Rumio ; coordinatore: Magda Enrica Gioia","M. 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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/week for 3 or 4 weeks led to a significantly increased survival-time as compared to controls and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Depletion of NK 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. However, daily i.p. administration of CpG-ODN induced a significant increase of survival-time but no cure of a single mouse, therefore we screened the effectiveness of CpG-ODN in combination with different agents, including bevacizumab, Poly(I):Poly(C) and cisplatin. Our data indicate that the combination of repeated i.p. CpG-ODN treatments plus bevacizumab and Poly(I):Poly(C) do not significantly increase median survival time, while the association of CpG-ODN and cisplatin revealed a significant increase in mice lifespan. Based on these results, we performed several experments in order to gain inside the molecular mechanisms by which CpG-ODN improves the therapeutic efficacy of cisplatin, a DNA-damaging drug. We demonstrate that an immunostimulatory Toll-like receptor-9 (TLR9) agonist CpG-oligodeoxynucleotide (CpG-ODN) oppositely modulates expression of DNA repair genes in tumor and immune cells. Analyses in silico and in a human ovarian tumor model by microarray revealed downregulation of these genes in tumors and upregulation in immune cells, with no detectable modulation in normal non-immune tissue. CpG-ODN induced activation of cells present in the tumor microenvironment was critical in inducing DNA-repair gene modulation in tumors. In conclusion, the combination of cisplatin with CpG-ODN was effective and well tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to down-modulate DNA repair genes in tumor cell."]},{"key":"dc:title","label":"Title","values":["LOCOREGIONAL DELIVERY OF UNMETHYLATED CPG-OLIGODEOXYNUCLEOTIDES TO CANCER THERAPY: PRECLINICAL STUDIES"]}]}],"canonical_facts":{"dc:contributor":["tutor: Cristiano Rumio ; coordinatore: Magda Enrica Gioia","M. Sommariva","RUMIO, CRISTIANO","GIOIA, MAGDA ENRICA"],"dc:creator":["M. Sommariva"],"dc:date":["2010-12-20"],"dc:description":["Tumor cell growth, even in advanced stages of ovarian cancer, is nearly always restricted to the peritoneal cavity, therefore repeated intraperitoneal injections of 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/week for 3 or 4 weeks led to a significantly increased survival-time as compared to controls and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Depletion of NK 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. However, daily i.p. administration of CpG-ODN induced a significant increase of survival-time but no cure of a single mouse, therefore we screened the effectiveness of CpG-ODN in combination with different agents, including bevacizumab, Poly(I):Poly(C) and cisplatin. Our data indicate that the combination of repeated i.p. CpG-ODN treatments plus bevacizumab and Poly(I):Poly(C) do not significantly increase median survival time, while the association of CpG-ODN and cisplatin revealed a significant increase in mice lifespan. Based on these results, we performed several experments in order to gain inside the molecular mechanisms by which CpG-ODN improves the therapeutic efficacy of cisplatin, a DNA-damaging drug. We demonstrate that an immunostimulatory Toll-like receptor-9 (TLR9) agonist CpG-oligodeoxynucleotide (CpG-ODN) oppositely modulates expression of DNA repair genes in tumor and immune cells. Analyses in silico and in a human ovarian tumor model by microarray revealed downregulation of these genes in tumors and upregulation in immune cells, with no detectable modulation in normal non-immune tissue. CpG-ODN induced activation of cells present in the tumor microenvironment was critical in inducing DNA-repair gene modulation in tumors. In conclusion, the combination of cisplatin with CpG-ODN was effective and well tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to down-modulate DNA repair genes in tumor cell."],"dc:identifier":["http://hdl.handle.net/2434/150068","10.13130/sommariva-michele_phd2010-12-20"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["IMMUNOTHERAPY","TOLL-LIKE RECEPTOR","CpG-ODN","OVARIAN CANCER","ASCITES","DNA REPAIR","Settore BIO/16 - Anatomia Umana","Settore BIO/17 - Istologia"],"dc:title":["LOCOREGIONAL DELIVERY OF UNMETHYLATED CPG-OLIGODEOXYNUCLEOTIDES TO CANCER THERAPY: PRECLINICAL STUDIES"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:19:15Z"}