부산대학교 도서관

Conatumumab is a monoclonal antibody specific for death receptor 5 DR5 that activates caspases leading to DNA fragmentation and tumorcell death. Like other Tumor Necrosis FactorRelated ApoptosisInducing Ligand TRAIL receptor therapies, conatumumab is currently being evaluated in clinical trials across a variety of tumor types. However, molecular evidence of ontarget drug activity in tumors is often an elusive goal for clinical investigation. Here we evaluated a translational approach using a relevant biopsy method, fine needle aspirates FNAs, to study the ontarget pharmacodynamics of conatumumab preclinically. As detected by laser scanning cytometry, druginduced caspase3 activation in FNA biopsies of Colo205 xenografts correlated well with activated caspase3 in conventional sectionbased samples. Furthermore, in tumorbearing mice, surrogate assays of serum caspase37 activity and serum drug exposure correlated with in situ caspase3 activation. We found that one advantage of FNA sampling over other sampling techniques was the ability to measure caspase activity on a per cell basis using DNA content information. To adapt the utility of FNAs for measuring pharmacodynamic markers in humans, detection of activated caspase3 was multiplexed with EpCAM to characterize mock and clinical FNAs from colorectal and nonsmall cell lung cancer patients. These data suggest that FNA sampling is a practical method to cytometrically evaluate tumors for pharmacological impact in a clinical setting. © 2010 International Society for Advancement of Cytometry