PubMed · 8484828
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J Kirpensteijn. 1993. Aural neoplasms.. https://pubmed.ncbi.nlm.nih.gov/8484828/
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Pancreatic adenocarcinoma has a rising incidence and a very poor survival rate. To develop new treatment strategies, extensive research is performed on animal models of pancreatic cancer. Orthotopic pancreatic tumors models, where the tumor is implanted into the pancreas, resemble the human disease more closely than subcutaneous tumor models, yet are difficult to monitor. In our study we report a magnetic resonance imaging (MRI) approach to visualize the pancreas in mice and to monitor orthotopically implanted pancreatic tumors. An MRI scanner was used to image normal murine pancreas and the pancreas of mice implanted with a human pancreatic adenocarcinoma cell line. Gadolinium (Gd)-DTPA-enhanced T1- and T2-weighted standard sequences were used with the objective to identify the pancreas and to monitor the growth of orthotopic tumors during 30 days. The pancreas as well as the implanted tumors could be easily identified using MRI. On T2-weighted images, the implanted tumors were easily visualized at the implantation side with high signal intensity. After application of a contrast agent, the tumors showed an enhancement. Heterogeneities within the tumor could be delineated, corresponding to histology, and the size of the tumor could be measured precisely. MR serves as a noninvasive high-resolution image modality to monitor murine pancreas as well as size, growth and even areas of heterogeneity in orthotopic pancreatic tumors.
Imatinib mesylate (Gleevec) inhibits the BCR-ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c-kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 +/- 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 +/- 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri-tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin.
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