PMID- 22623209
OWN - NLM
STAT- MEDLINE
DCOM- 20121105
LR  - 20211021
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 70
IP  - 3
DP  - 2012 Sep
TI  - AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation 
      in neuroblastoma xenografts.
PG  - 477-86
LID - 10.1007/s00280-012-1879-x [doi]
AB  - Neuroblastoma is a common pediatric tumor characterized by clinical 
      heterogeneity. Because it is derived from sympathetic neuroblasts, the NTRK 
      family of neurotrophin receptors plays an integral role in neuroblastoma cell 
      survival, growth, and differentiation. Indeed, high expression of NTRK1 is 
      associated with favorable clinical features and outcome, whereas expression of 
      NTRK2 and its ligand, brain-derived neurotrophic factor (BDNF), are associated 
      with unfavorable features and outcome. AZ64 (Astra Zeneca) is a potent and 
      selective inhibitor of the NTRK tyrosine kinases that blocks phosphorylation at 
      nanomolar concentrations. To determine the preclinical activity of AZ64, we 
      performed intervention trials in a xenograft model with NTRK2-overexpressing 
      neuroblastomas. AZ64 alone significantly inhibited tumor growth compared to 
      vehicle-treated animals (p = 0.0006 for tumor size). Furthermore, the combination 
      of AZ64 with conventional chemotherapeutic agents, irinotecan and temozolomide 
      (irino-temo), showed significantly enhanced anti-tumor efficacy compared to 
      irino-temo alone [(p < 0.0001 for tumor size, p < 0.0005 for event-free survival 
      (EFS)]. We also assessed the combination of AZ64 and local radiation therapy (RT) 
      on a neuroblastoma hindlimb xenograft model, and the efficacy of local RT was 
      significantly increased when animals were treated simultaneously with AZ64 (p < 
      0.0001 for tumor size, p = 0.0006 for EFS). We conclude that AZ64 can inhibit 
      growth of NTRK-expressing neuroblastomas both in vitro and in vivo. More 
      importantly, it can significantly enhance the efficacy of conventional 
      chemotherapy as well as local RT, presumably by inhibition of the NTRK2/BDNF 
      autocrine survival pathway.
FAU - Iyer, Radhika
AU  - Iyer R
AD  - Division of Oncology, Children's Hospital of Philadelphia, PA 19104-4302, USA.
FAU - Varela, Carly R
AU  - Varela CR
FAU - Minturn, Jane E
AU  - Minturn JE
FAU - Ho, Ruth
AU  - Ho R
FAU - Simpson, Anisha M
AU  - Simpson AM
FAU - Light, Jennifer E
AU  - Light JE
FAU - Evans, Audrey E
AU  - Evans AE
FAU - Zhao, Huaqing
AU  - Zhao H
FAU - Thress, Kenneth
AU  - Thress K
FAU - Brown, Jeffrey L
AU  - Brown JL
FAU - Brodeur, Garrett M
AU  - Brodeur GM
LA  - eng
GR  - P01 CA097323/CA/NCI NIH HHS/United States
GR  - R01 CA094194/CA/NCI NIH HHS/United States
GR  - CA-097323/CA/NCI NIH HHS/United States
GR  - CA-094194/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120524
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 7673326042 (Irinotecan)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - XT3Z54Z28A (Camptothecin)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Camptothecin/administration & dosage/analogs & derivatives
MH  - Cell Line, Tumor
MH  - Combined Modality Therapy
MH  - Dacarbazine/administration & dosage/analogs & derivatives
MH  - Disease-Free Survival
MH  - Humans
MH  - Irinotecan
MH  - Mice
MH  - Mice, Nude
MH  - Neuroblastoma/*drug therapy/pathology/radiotherapy
MH  - Receptor, trkB/*antagonists & inhibitors
MH  - Temozolomide
MH  - Xenograft Model Antitumor Assays
PMC - PMC4242714
MID - NIHMS643539
EDAT- 2012/05/25 06:00
MHDA- 2012/11/06 06:00
PMCR- 2014/11/24
CRDT- 2012/05/25 06:00
PHST- 2011/11/09 00:00 [received]
PHST- 2012/04/30 00:00 [accepted]
PHST- 2012/05/25 06:00 [entrez]
PHST- 2012/05/25 06:00 [pubmed]
PHST- 2012/11/06 06:00 [medline]
PHST- 2014/11/24 00:00 [pmc-release]
AID - 10.1007/s00280-012-1879-x [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2012 Sep;70(3):477-86. doi: 
      10.1007/s00280-012-1879-x. Epub 2012 May 24.