Combination of metronomic gimatecan and CpG-oligodeoxynucleotides against an orthotopic pancreatic cancer xenograft.
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 (0.25 mg/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 microg/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 CpG-ODN 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.
Petrangolini
Giovanna
G
Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Tortoreto
Monica
M
Perego
Paola
P
Carenini
Nives
N
De Cesare
Michelandrea
M
Balsari
Andrea
A
Zunino
Franco
F
Pratesi
Graziella
G
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D019772:Topotecan / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C433984:ST 1481; D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan; D002166:Camptothecin