Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

Abstract

Abstract. Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer.

A Study Comparing the Effects of Targeted Intra-Arterial and Systemic Chemotherapy in an Orthotopic Mouse Model of Pancreatic Cancer

“…Hence, we used 0.3 mg/kg of gemcitabine as our treatment dose for our experimental groups. Although this dose was significantly lower than what has been used in previous small animal studies for IV administration, which range from 2 to 240 mg/kg 38,39 , we found that when this dose was given IA to mice with orthotopic pancreatic tumors there was a reduction in tumor growth when compared to the same dose administered IV. Indeed, in order to achieve the same therapeutic effect as IA administration, gemcitabine needed to be administered systemically by IV injection at over 300 times the dose thereby demonstrating the efficacy of this approach for the treatment of pancreatic cancer.…”

“…Previous studies have shown that the therapeutic concentration of gemcitabine when given systemically to small animal models is in the range of 2–240 mg/kg 38,39 . To determine a concentration of gemcitabine which would be safe to give IA directly into the pancreas, in nude mice, a dose study was performed in which 24 nude mice (n = 3 per group) were given different gemcitabine concentrations (50, 30, 15, 5, 1, 0.5, 0.3 and 0.2 mg/kg) once a week for two weeks.…”

Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma

“…For the antitumor study using orthotopic model, NNPs/CLT treatment group showed no obvious toxicity to major organs compared to CLT solution group. Orthotopic pancreatic cancer models have been reported to develop metastasis to adjacent organs such as liver and gastrointestinal tract34., 35.. In our study, saline, CLT solution, and NPs/CLT all showed obvious liver metastases with dense nuclei clusters representing tumor cells (Fig.…”

“…For the antitumor study using orthotopic model, NNPs/CLT treatment group showed no obvious toxicity to major organs compared to CLT solution group. Orthotopic pancreatic cancer models have been reported to develop metastasis to adjacent organs such as liver and gastrointestinal tract 34. , 35.…”

“…Then, the severity of pancreatitis based on edema, inflammation, leukocyte infiltration, alveolar wall thickening and collapse, vacuolization vascular congestion and destruction of alveolar wall, all of these can be seen. Histological evaluation of pulmonary injury was assessed for interstitial and intraalveolar leukocyte infiltrations, interstitial and intraalveolar edema, and fibrosis as previously described 34 .…”