Combination of metronomic gimatecan and CpG-oligodeoxynucleotides against an orthotopic pancreatic cancer xenograft

Giovanna Petrangolini, Monica Tortoreto, Paola Perego, Nives Carenini, Michelandrea De Cesare, Andrea Balsari, Franco Zunino, Graziella Pratesi

Research output: Contribution to journalArticlepeer-review

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 (0.25 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 μg/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.

Original languageEnglish
Pages (from-to)596-601
Number of pages6
JournalCancer Biology and Therapy
Volume7
Issue number4
Publication statusPublished - Apr 2008

Keywords

  • Animal models
  • Camptothecin
  • CpG-oligodeoxynucleotide
  • Gimatecan
  • Metronomic chemotherapy
  • Pancreatic cancer
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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