Biomarkers and Personalized Medicine clinical and Clinical Estimates of the Basal Apoptotic Rate Cancer Predict the Amount of Apoptosis Induced R ubsequent Proapoptotic Stimuli

Downloa pose: We hypothesized that the basal apoptotic rate (BAR) of a cancer would predict sensitivity sequent proapoptotic stimuli. To explore this, preclinical and clinical BAR assays were developed ring cumulative apoptotic events through ELISAs for soluble caspase-cleaved cytokeratin 18 (M30) lized to either cell number increase or total tumor volume, respectively. erimental Design: The BARs of A549, HCC44, and SW1573 non–small cell lung carcinoma cell were measured following different pro/antiapoptotic manipulations. In isogenic wild-type and knockdown (KD) series, pretreatment BARs were correlated with response to proapoptotic stimuli ompared with established apoptosis assays. Pretreatment and posttreatment serum was available stereotactic body radiation therapy patients. ults: Caspase inhibition and p53 KDs reduced the BAR, whereas serum deprivation, XIAP, or Bcl2 creased the BAR. The nontreated BAR rank ordering of the XIAP series recapitulated that with terdeoxynucleotidyl transferase–mediated dUTP nick end labeling and caspase-3/7 activity assays, and ted each line's sensitivity to TRAIL or irradiation. Terminal deoxynucleotidyl transferase–mediated nick end labeling, however, underestimated basal apoptosis during increased apoptotic stress, and e-3/7 activity detected minimal death in the media. P53 KDs with lower nontreated BARs were less ive to TRAIL and cisplatinum than wild-type. Stereotactic body radiation therapy increased serum alues, and the pretreatment clinical BAR strongly correlated with fold change in M30 on treatment .93). clusions: M30-based BAR assays reflect apoptosis accurately and are more amenable to clinical ation than existing apoptosis assays. The pretreatment BAR correlates with cell and/or tumor sensiapplic tivity to extrinsic and intrinsic apoptotic pathway stimulation. Prospective clinical exploration is warranted.