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Measurement of conatumumab‐induced apoptotic activity in tumors by fine needle aspirate sampling
Author(s) -
Zoog Stephen J.,
Ma Connie Y.,
KaplanLefko Paula J.,
Hawkins Jennifer M.,
Moriguchi Jodi,
Zhou Lei,
Pan Yang,
Hsu ChengPang,
Friberg Greg,
Herbst Roy,
Hill John,
Juan Gloria
Publication year - 2010
Publication title -
cytometry part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.316
H-Index - 90
eISSN - 1552-4930
pISSN - 1552-4922
DOI - 10.1002/cyto.a.20940
Subject(s) - flow cytometry , dna fragmentation , apoptosis , caspase , cancer research , pharmacodynamics , programmed cell death , caspase 3 , medicine , pathology , biology , immunology , pharmacology , pharmacokinetics , biochemistry
Conatumumab is a monoclonal antibody specific for death receptor 5 (DR5) that activates caspases leading to DNA fragmentation and tumor‐cell death. Like other Tumor Necrosis Factor‐Related Apoptosis‐Inducing Ligand (TRAIL) receptor therapies, conatumumab is currently being evaluated in clinical trials across a variety of tumor types. However, molecular evidence of on‐target 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 on‐target pharmacodynamics of conatumumab pre‐clinically. As detected by laser scanning cytometry, drug‐induced caspase‐3 activation in FNA biopsies of Colo205 xenografts correlated well with activated caspase‐3 in conventional section‐based samples. Furthermore, in tumor‐bearing mice, surrogate assays of serum caspase‐3/7 activity and serum drug exposure correlated with in situ caspase‐3 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 caspase‐3 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