Abstract 3800: Nitric oxide acts a promoter of the enhanced permeation and retention effect in a xenograft pancreatic carcinoma model (2012)

Abstract Pancreatic cancer is the forth most common cause of cancer death worldwide and today there is no effective treatment. Gemcitabine and 5-fluorouracil have been approved for this indication, but merely show a poor response rate with a small benefit in overall survival. The use of albumin as a carrier for drugs is a potential therapeutic option for the treatment of this tumor indication, and we could recently show that INNO-206, an albumin-binding prodrug of doxorubicin under clinical evaluation, produces significant tumor growth inhibition and reduction of metastases in an orthotopic tumor model in mice (Graeser et al. Invest. New Drugs 2009, 28, 14-19). Since important benefits of drug-albumin conjugates can be attributed to the enhanced permeability and retention of the tumor vasculature (also known as the EPR effect), we were interested in how to further enhance this effect in pancreatic tumors which generally only exhibit a moderate vascularization. Maeda and co-workers have described three methods of EPR alteration: by the use of donors of nitric oxide such as nitroglycerin, by temporarily elevating the blood pressure with angiotensin II, and by treatment with a kininase II inhibitor such as enalapril in combination with angiotensin II. Thus, we set out to compare these methods in the MiaPaCa-2 xenograft model in nude mice. Instead of angiotensin II which has a very short half-life of a few seconds, we used the longer acting peptide endothelin I for inducing hypertension. The tumor-bearing mice were treated with nitroglycerin (topically, 1 mg per tumor), with endothelin I (3.7 µg/kg), and with enalapril (10 mg/kg) in combination with endothelin I (3.7 µg/kg) followed by an injection of the dye Evans Blue (10 mg/kg) which strongly binds to serum albumin thus forming a stable dye-albumin complex. Animals were sacrificed after 1 h, 6 h, 24 h, 48 h, and 168 h, respectively, and the tumors were dissected. The concentration of Evans Blue was determined after extraction of the tumor tissue with formamide. The lowest concentrations of Evans Blue correlating with respect to tumor uptake of serum albumin were found in the control group as well as the group treated with endothelin I. Higher levels of the dye were found in the mice treated with the combination enalapril/endothelin I whereas the highest concentrations were found after treatment with nitroglycerin. Generally, the concentrations of the dye increased with time and reached a maximum at the end of the experiment. These results indicate that vascular permeability for albumin can be enhanced most effectively by the NO donor nitroglycerin in mice bearing pancreas tumor xenografts. This seems to be a viable method for enhancing the EPR effect that is worthy of further investigation also with other nitric oxide releasing drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3800. doi:1538-7445.AM2012-3800