Abstract
Abstract Aldose reductase (AKR1B1) mediates the first and rate limiting step in the conversion of glucose to polyols that contribute to redox imbalance, formation of reactive oxygen species, and activation of signal transduction pathways that can promote tumor formation and tumor growth. Aldose reductases are overexpressed in a variety of human tumors, and genetic or pharmacological blockade of AKR1B1 has been reported to attenuate these processes. CP-744809 is a highly potent and selective aldose reductase enzyme inhibitor which has been previously shown to provide efficacy in an experimental model of diabetic retinopathy. The compound has properties of high oral bioavailability, very high protein binding, and a very long half life in vivo. In this study, we have characterized the activity of this agent in animal models of angiogenesis and tumor growth. CP-744809 treatment significantly reduced VEGF-induced angiogenesis in a dose-dependent manner in the rat corneal micropocket assay, suggesting a heretofore unrecognized role for aldose reductase in this process. Interestingly, when the related aldose reductase inhibitor Zopolrestat was administered to normal rats, a significantly decreased level of the angiogenic lipid mediator sphingosine-1-phosphate was observed along with other lipid changes. In xenograft models, the CP-744809 treatment was associated with significant and reproducible reduction in tumor size that was dose dependent and superior to treatment with Zopolrestat. Final tumor mass in individual animals was highly correlated with the corresponding intratumoral drug concentration. In contrast, drug concentrations in serum were poorly correlated with drug concentrations in tumor or with tumor mass. Serum drug concentrations at every dose were consistently 7-10 fold higher than those observed in tumor, suggesting a barrier to optimal penetration of tumor tissue by the compound. Pooling data from multiple in vivo studies, the total intra-tumoral drug concentration (protein bound and unbound) required to achieve half maximal efficacy (EC50) was estimated to be 77 micrograms/ml. These results confirm the therapeutic potential of aldose reductase as an interesting cancer target, and have uncovered a novel antiangiogenic activity. They also highlight the obstacle that adequate tumor tissue penetration may pose for clinical development of agents such as CP-744809. Combination treatments with other agents are being evaluated to assess the potential for synergistic activity with the vascular and inflammation modulating properties of aldose reductase inhibitors. 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 4540.
Published Version
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