The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism,vascular function,cell proliferation,and tumor growth |
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Authors: | Donald T Yapp May Q Wong Alastair H Kyle Shannon M Valdez Jenny Tso Andrew Yung Piotr Kozlowski David A Owen Andrzej K Buczkowski Stephen W Chung Charles H Scudamore Andrew I Minchinton Sylvia S W Ng |
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Institution: | 1.Department of Experimental Therapeutics,British Columbia Cancer Agency,Vancouver,Canada;2.Faculty of Pharmaceutical Sciences,University of British Columbia,Vancouver,Canada;3.Integrative Oncology,British Columbia Cancer Agency,Vancouver,Canada;4.Magnetic Resonance Imaging Research Centre,University of British Columbia,Vancouver,Canada;5.Pathology and Laboratory Medicine,University of British Columbia,Vancouver,Canada;6.Department of Surgery, Faculty of Medicine,University of British Columbia,Vancouver,Canada;7.The Department of Radiation Oncology,Princess Margaret Cancer Centre,Toronto,Canada |
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Abstract: | BackgroundMetronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.MethodsTwo primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments.ResultsTumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors’ avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor’s vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.ConclusionThe aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident. |
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