st-1481 and Pancreatic-Neoplasms

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Humans; Mice; Mice, Nude; Oligodeoxyribonucleotides; Pancreatic Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays

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.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Cell Line, Tumor; Female; Humans; Mice; Mice, Nude; Oligodeoxyribonucleotides; Pancreatic Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Topotecan; Xenograft Model Antitumor Assays