PMID- 15746061
OWN - NLM
STAT- MEDLINE
DCOM- 20050728
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 11
IP  - 4
DP  - 2005 Feb 15
TI  - The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, 
      sensitizes small cell lung cancer cell lines to the effects of chemotherapy.
PG  - 1563-71
AB  - PURPOSE: Insulin-like growth factor-I (IGF-I) is a potent growth factor for small 
      cell lung cancer (SCLC) in both the autocrine and endocrine context. It also 
      inhibits chemotherapy-induced apoptosis through activation of the 
      phosphatidylinositol 3-kinase (PI3K)-Akt pathway and we have previously shown 
      that inhibition of this signaling pathway enhances sensitivity of SCLC cell lines 
      to chemotherapy. The purpose of this study was to determine whether the novel 
      IGF-I receptor (IGF-IR) kinase inhibitor, NVP-ADW742, sensitizes SCLC cell lines 
      to etoposide and carboplatin, which are commonly used in the treatment of SCLC. 
      EXPERIMENTAL DESIGN: Cell growth in the presence of various combinations of 
      NVP-ADW742, imatinib (STI571; Gleevec/Glivec), and chemotherapeutic agents was 
      monitored using a 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide 
      (MTT) assay and analyzed using the Chou-Talalay multiple-drug-effect equation. 
      Induction of apoptosis was assessed using terminal deoxynucleotide 
      transferase-mediated dUTP nick end labeling (TUNEL) and Western blot analysis of 
      procaspase 3 and poly(ADP-ribose)polymerase cleavage. IGF-I-induced vascular 
      endothelial cell growth factor expression was monitored by Northern blot and 
      ELISA. RESULTS: NVP-ADW742 synergistically enhanced sensitivity of multiple SCLC 
      cell lines to etoposide and carboplatin. Maximal enhancement occurred at 
      concentrations of NVP-ADW742 that eliminated basal PI3K-Akt activity in 
      individual cell lines. In the WBA cell line, in which the c-Kit receptor tyrosine 
      kinase is partly responsible for basal PI3K-Akt activity, the combination of 
      NVP-ADW742 and imatinib was superior to NVP-ADW742 alone in sensitizing the cells 
      to etoposide. Enhancement of the sensitivity of SCLC cell lines to etoposide, as 
      determined by MTT assay, correlated closely with sensitization to the induction 
      of apoptosis as measured by TUNEL and caspase activation assays. Treatment with 
      NVP-ADW742 also eliminated IGF-I-mediated expression of vascular endothelial cell 
      growth factor, suggesting that in addition to enhancing sensitivity of SCLC to 
      chemotherapy, this kinase inhibitor could potentially inhibit angiogenesis in 
      vivo. CONCLUSIONS: Inhibition of IGF-IR signaling synergistically enhances the 
      sensitivity of SCLC to etoposide and carboplatin. This enhancement in sensitivity 
      to chemotherapy tightly correlates with inhibition of PI3K-Akt activation. Future 
      SCLC clinical trials incorporating IGF-IR inhibitors alone or in combination with 
      other kinase inhibitors should include assessment of PI3K-Akt activity as a 
      pharmacodynamic end-point.
FAU - Warshamana-Greene, G Sakuntala
AU  - Warshamana-Greene GS
AD  - Department of Medicine, Virginia Commonwealth University and McGuire Veterans 
      Affairs Medical Center, Richmond, VA 23249, USA.
FAU - Litz, Julie
AU  - Litz J
FAU - Buchdunger, Elisabeth
AU  - Buchdunger E
FAU - Garcia-Echeverria, Carlos
AU  - Garcia-Echeverria C
FAU - Hofmann, Francesco
AU  - Hofmann F
FAU - Krystal, Geoffrey W
AU  - Krystal GW
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
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 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - BG3F62OND5 (Carboplatin)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - MXS2N5862L (NVP ADW742)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Carboplatin/*pharmacology
MH  - Carcinoma, Small Cell/drug therapy/pathology
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Etoposide/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Lung Neoplasms/drug therapy/metabolism/pathology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Pyrimidines/*pharmacology
MH  - Pyrroles/*pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptor, IGF Type 1/*antagonists & inhibitors/metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/metabolism
EDAT- 2005/03/05 09:00
MHDA- 2005/07/29 09:00
CRDT- 2005/03/05 09:00
PHST- 2005/03/05 09:00 [pubmed]
PHST- 2005/07/29 09:00 [medline]
PHST- 2005/03/05 09:00 [entrez]
AID - 11/4/1563 [pii]
AID - 10.1158/1078-0432.CCR-04-1544 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2005 Feb 15;11(4):1563-71. doi: 10.1158/1078-0432.CCR-04-1544.