Abstract
Abstract Introduction: Pancreatic cancer is clinically resistant to chemotherapy and radiation therapy, and newer targeted therapies have not remarkably improved survival. In a phase III trial, the addition of bevacizumab to the gemcitabine-erlotinib combination significantly increased survival vs. the the gemcitabine-erlotinib combination alone in pancreatic cancer patients (van Cutsem et al, JCO, 2009). This suggests that the vasculature in pancreatic tumors is a valid therapeutic target. It has been shown that antiangiogenic agents ‘normalize’ vascular function, and improve drug delivery to the tumor. Interestingly, data from our group indicated that metronomic chemotherapy regimens may have similar effects. The objective of the present study was to compare the effects of DC101, a dedicated antiangiogenic drug, and metronomic dosing of gemcitabine (Met-Gem) on the vascular function and metabolic activity of primary pancreatic tumors. Method: Primary pancreatic tumors were grown orthotopically in SCID mice and treated with the vehicle control (0.9% saline), DC101 (800 ug, q3d, i.p.) or Met-Gem (30mg/kg, q3d, i.p.) for three weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and 18F-Fluorodeoxygluose positron emission tomography (18F-FDG PET) were used to assess tumor perfusion and metabolism in situ, respectively, on days 3, 7 and 21 after treatment was initiated. Tumors were harvested at each time point after imaging. Immunofluorescence staining was performed on tumor cryosections followed by computerized image analysis to determine cell proliferation, apoptosis, and vessel density. Results: On day 21, Met-Gem and DC101 reduced tumor volume by 97% (P<0.05) and 26% (P<0.05), respectively, compared to the vehicle control. 18F-FDG uptake was increased by 23% (P<0.05) after DC101 treatment, but decreased by 35% (P<0.05) following Met-Gem therapy. Ktrans values derived from DCE MRI indicated that Met-Gem-treated tumors were more perfused (+114%; P <0.05) on day 7, but subsequently became less so on day 21 (−47%; P<0.05). No significant changes in perfusion were observed with DC101 treatment. Immunostaining data showed that the percentage of CD31+ pixels was reduced by DC101 (−35%; P<0.05), but increased by Met-Gem (+38%; P<0.05), compared to the vehicle control. In addition, the average distance between blood vessels increased with DC101 (+53%; P<0.05), but decreased with Met-Gem (−45%; P<0.05) treatment, respectively. Conclusion: Metronomic dosing of gemcitabine is more effective in controlling tumor growth, improving overall tumor perfusion, and reducing the overall metabolic activity in primary pancreatic adenocarcinoma compared to DC101. Based on these data, we postulate that using metronomic gemcitabine in combination therapies for pancreatic cancer may improve treatment efficacy by optimizing drug delivery to the cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1296.
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