Abstract B22: IT-141, a stabilized polymer micelle formulation, prolongs the pharmacodynamic effect of SN-38

IT-141 is a formulation of SN-38 encapsulated in an iron-stabilized polymer micelle. SN-38 is the active metabolite of irinotecan (CPT-11) which in combination with 5-FU and leucovorin is first-line FDA approved therapy for metastatic colorectal cancer. Although SN-38 is 1,000 times more potent than irinotecan alone, there is about 100-fold lower concentration of SN-38 in plasma from irinotecan. In the clinic only 2% to 10% of the administered dose of irinotecan is converted by carboxylesterases to SN-38 and there is great interpatient variability with toxicity. In vitro, IT-141 demonstrated nanomolar IC50s against a panel of human cancer cell lines in comparison to irinotecan's micromolar IC50 concentrations. SN-38 binds to the topoisomerase I-DNA complex resulting in double stranded breaks and cell death. We compared the mechanism of action of IT-141 compared to irinotecan treatment in HT-29 xenografts tumors. We demonstrated the incidence of double stranded breaks by immunohistochemistry (IHC) of - H2AX expression in tumors treated with IT-141 compared to irinotecan treatment at different time points (24, 48, 72 and 144 hours). In irinotecan treated tumors, - H2AX expression peaked at 72 hours followed by a sharp decrease in expression at 144 hours. In IT-141 treated tumors, - H2AX positive staining increased steadily from 24 through 144 hours. This shift in the kinetics of the mechanism corroborates the biodistribution studies where IT-141 delivered 34-fold more SN-38 to ...

Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sethuraman, J., Costich, T. L., Carie, A., Buley, T., Ellis, T., Semple, J. E., Vojkovsky, T., Sill, K., Bakewell, S. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research