Establishment of a new valid animal model for the evaluation of
hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric
rhabdomyosarcoma
Abstract
Background: Cytoreductive surgery in combination with hyperthermic
intraperitoneal chemotherapy has been established as a novel treatment
approach for peritoneal sarcomatosis. Despite promising clinical
reports, there is still a lack of knowledge regarding optimal drug usage
and local effects. Therefore, we intended to establish a murine animal
model for further evaluation. Procedure: Alveolar rhabdomyosarcoma cells
were xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice
received a continuous intraperitoneal lavage with isotonic saline
solution as control- or with cisplatin (30 or 60 mg/m2) as treatment
group for 60 minutes at 37 or 42 °C (6 subgroups, each n=16). Tumor
spread was documented by an adapted peritoneal cancer index and MRI
(n=4). Tumor and tissue samples, harvested at the end of the perfusion,
were evaluated regarding morphology, proliferation and apoptosis (H&E-,
Ki-67-, Cleaved Caspase 3-staining, TUNEL-assay). Results: Extensive
peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC
was feasible without acute side effects. Ki-67 staining revealed
concentration- or temperature-dependent effects of cisplatin-based HIPEC
on the tumors. While Cleaved Caspase-3 showed only sporadic apoptotic
effects. TUNEL-assay detected concentration- or temperature-dependent
apoptotic effects at the outer tumor surface. MRI scans confirmed the
observed tumor dissemination. Conclusion: This is the first animal model
for evaluation of HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC
had early effects on the proliferation whereas circumscribed apoptotic
effects could be detected at the tumor surface. This model allows
further insights on the possible efficiency of HIPEC in RMS. Further
studies using other drug combinations and treatment will follow.