Gimatecan, a potent lipophilic camptothecin, is active by oral route, which allows a comparison of different treatment schedules. The present study was designed based on previous evidence of improved antitumor efficacy of the combination of topotecan with immunostimulatory CpG-ODN. Two regimens of gimatecan, i.e. a low-dose/protracted treatment (metronomic) and a high-dose/intermittent treatment, were compared in the GER orthotopic human pancreatic tumor model in nude mice. Metronomic gimatecan (0.25mg/kg per os, daily) significantly increased mice survival time over control mice (154 T/C%, P<0.05), in contrast to intermittent treatment-gimatecan (1.5 mg/kg per os, q4d) or intravenous gemcitabine (125 and 128 T/C%, respectively, P>0.1). Metronomic gimatecan combined to CpG-ODN (20 mug/mouse intraperitoneal, weekly) was well tolerated and achieved a strong antitumor effect, with a T/C% of 188 on survival time (P<0.001 versus control mice), significantly superior to those of the single agent-treated mice (P<0.05 versus gimatecan- or CpG-ODN-treated mice). Cellular studies indicated that TRAIL could increase the apoptotic response to gimatecan in GER tumor cells, and TRAIL was released in the peritoneal washings of CpG-ODN-treated mice. In conclusion, the combination of metronomic gimatecan with CpGODN was effective and tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to stimulate TRAIL release and the high level of TRAIL-receptors expressed in pancreatic tumor cells.
Combination of metronomic gimatecan and CpG-oligodeoxynucleotides agains an orthotopic pancreatic cancer xenograft / G. Petrangolini, M. Tortoreto, P. Perego, N. Carenini, M. De Cesare, A. Balsari, F. Zunino, G. Pratesi. - In: CANCER BIOLOGY & THERAPY. - ISSN 1538-4047. - 7:4(2008 Apr), pp. 596-601. [10.4161/cbt.7.4.5548]
Combination of metronomic gimatecan and CpG-oligodeoxynucleotides agains an orthotopic pancreatic cancer xenograft
A. Balsari;
2008
Abstract
Gimatecan, a potent lipophilic camptothecin, is active by oral route, which allows a comparison of different treatment schedules. The present study was designed based on previous evidence of improved antitumor efficacy of the combination of topotecan with immunostimulatory CpG-ODN. Two regimens of gimatecan, i.e. a low-dose/protracted treatment (metronomic) and a high-dose/intermittent treatment, were compared in the GER orthotopic human pancreatic tumor model in nude mice. Metronomic gimatecan (0.25mg/kg per os, daily) significantly increased mice survival time over control mice (154 T/C%, P<0.05), in contrast to intermittent treatment-gimatecan (1.5 mg/kg per os, q4d) or intravenous gemcitabine (125 and 128 T/C%, respectively, P>0.1). Metronomic gimatecan combined to CpG-ODN (20 mug/mouse intraperitoneal, weekly) was well tolerated and achieved a strong antitumor effect, with a T/C% of 188 on survival time (P<0.001 versus control mice), significantly superior to those of the single agent-treated mice (P<0.05 versus gimatecan- or CpG-ODN-treated mice). Cellular studies indicated that TRAIL could increase the apoptotic response to gimatecan in GER tumor cells, and TRAIL was released in the peritoneal washings of CpG-ODN-treated mice. In conclusion, the combination of metronomic gimatecan with CpGODN was effective and tolerated, and might represent a preclinical basis for the design of clinical studies, even considering the ability of CpG-ODN to stimulate TRAIL release and the high level of TRAIL-receptors expressed in pancreatic tumor cells.Pubblicazioni consigliate
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