CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft. Chemotherapy consisted of the maximum tolerated dose of gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 microg/mouse), weekly, after the end of chemotherapy. CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset (palpable i.p. tumor) and of bulky disease development (extensive peritoneal tumor burden), but did not enhance survival time. When the gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus gemcitabine-treated mice). Autoptic examination showed that tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the tumor response. The clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.

Therapeutic synergism of gemcitabine and CpG-oligodeoxynucleotides in an orthotopic human pancreatic carcinoma xenograft / G. Pratesi, G. Petrangolini, M. Tortoreto, A.M. Addis, S. Belluco, A. Rossini, S. Selleri, C. Rumio, S. Menard, A. Balsari. - In: CANCER RESEARCH. - ISSN 0008-5472. - 65:14(2005), pp. 6388-6393.

Therapeutic synergism of gemcitabine and CpG-oligodeoxynucleotides in an orthotopic human pancreatic carcinoma xenograft

A.M. Addis;S. Belluco;S. Selleri;C. Rumio;A. Balsari
Ultimo
2005

Abstract

CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft. Chemotherapy consisted of the maximum tolerated dose of gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 microg/mouse), weekly, after the end of chemotherapy. CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset (palpable i.p. tumor) and of bulky disease development (extensive peritoneal tumor burden), but did not enhance survival time. When the gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus gemcitabine-treated mice). Autoptic examination showed that tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the tumor response. The clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.
CpG island ; animal experiment ; animal model ; animal tissue ; antineoplastic activity ; article ; cancer inhibition ; cancer survival ; cellular immunity ; controlled study ; drug potency ; drug potentiation ; drug receptor binding ; drug tolerability ; female ; gene expression ; immunostimulation ; maximum tolerated dose ; mouse ; nonhuman ; nude mouse ; orthotopic transplantation ; pancreas carcinoma ; peritoneum metastasis ; priority journal ; treatment outcome ; tumor xenograft ; gemcitabine ; immunostimulating agent ; oligodeoxynucleotide derivative ; toll like receptor 9 ; gemzar
Settore VET/09 - Clinica Chirurgica Veterinaria
Settore MED/04 - Patologia Generale
Settore BIO/16 - Anatomia Umana
http://cancerres.aacrjournals.org/cgi/content/full/65/14/6388
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/27507
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