PMID- 20630997
OWN - NLM
STAT- MEDLINE
DCOM- 20110228
LR  - 20121115
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 17
DP  - 2010 Sep 1
TI  - Preclinical and clinical estimates of the basal apoptotic rate of a cancer 
      predict the amount of apoptosis induced by subsequent proapoptotic stimuli.
PG  - 4478-89
LID - 10.1158/1078-0432.CCR-10-0859 [doi]
AB  - PURPOSE: We hypothesized that the basal apoptotic rate (BAR) of a cancer would 
      predict sensitivity to subsequent proapoptotic stimuli. To explore this, 
      preclinical and clinical BAR assays were developed measuring cumulative apoptotic 
      events through ELISAs for soluble caspase-cleaved cytokeratin 18 (M30) normalized 
      to either cell number increase or total tumor volume, respectively. EXPERIMENTAL 
      DESIGN: The BARs of A549, HCC44, and SW1573 non-small cell lung carcinoma cell 
      lines were measured following different pro/antiapoptotic manipulations. In 
      isogenic wild-type and stable knockdown (KD) series, pretreatment BARs were 
      correlated with response to proapoptotic stimuli and compared with established 
      apoptosis assays. Pretreatment and posttreatment serum was available from 
      stereotactic body radiation therapy patients. RESULTS: Caspase inhibition and p53 
      KDs reduced the BAR, whereas serum deprivation, XIAP, or Bcl2 KDs increased the 
      BAR. The nontreated BAR rank ordering of the XIAP series recapitulated that with 
      terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and 
      caspase-3/7 activity assays, and predicted each line's sensitivity to TRAIL or 
      irradiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end 
      labeling, however, underestimated basal apoptosis during increased apoptotic 
      stress, and caspase-3/7 activity detected minimal death in the media. P53 KDs 
      with lower nontreated BARs were less sensitive to TRAIL and cisplatinum than 
      wild-type. Stereotactic body radiation therapy increased serum M30 values, and 
      the pretreatment clinical BAR strongly correlated with fold change in M30 on 
      treatment (r = 0.93). CONCLUSIONS: M30-based BAR assays reflect apoptosis 
      accurately and are more amenable to clinical application than existing apoptosis 
      assays. The pretreatment BAR correlates with cell and/or tumor sensitivity to 
      extrinsic and intrinsic apoptotic pathway stimulation. Prospective clinical 
      exploration is warranted.
FAU - Zhang, Lian
AU  - Zhang L
AD  - Department of Pharmacology, University of Colorado, School of Medicine, Aurora, 
      CO, USA.
FAU - Kavanagh, Brian D
AU  - Kavanagh BD
FAU - Thorburn, Andrew M
AU  - Thorburn AM
FAU - Camidge, D Ross
AU  - Camidge DR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100714
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Keratin-18)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (X-Linked Inhibitor of Apoptosis Protein)
RN  - 0 (XIAP protein, human)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Caspase 3/*metabolism
MH  - Caspase Inhibitors
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Humans
MH  - Immunoblotting
MH  - In Situ Nick-End Labeling
MH  - Keratin-18/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/drug therapy/*metabolism/pathology
MH  - Prognosis
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - RNA Interference
MH  - Signal Transduction/drug effects
MH  - Tumor Suppressor Protein p53/genetics/metabolism
MH  - X-Linked Inhibitor of Apoptosis Protein/genetics/metabolism
EDAT- 2010/07/16 06:00
MHDA- 2011/03/01 06:00
CRDT- 2010/07/16 06:00
PHST- 2010/07/16 06:00 [entrez]
PHST- 2010/07/16 06:00 [pubmed]
PHST- 2011/03/01 06:00 [medline]
AID - 1078-0432.CCR-10-0859 [pii]
AID - 10.1158/1078-0432.CCR-10-0859 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Sep 1;16(17):4478-89. doi: 10.1158/1078-0432.CCR-10-0859. 
      Epub 2010 Jul 14.