Abstract | PURPOSE: EXPERIMENTAL DESIGN: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib, vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway phosphorylation, soft- agar growth, motility, and vascular endothelial growth factor expression levels. RESULTS: Treatment with ADW742 induced down-regulation of IGF1R/AKT/ mammalian target of rapamycin (mTOR) phosphorylation, which was deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation (IC50 = 0.55-1.4 micromol/L), inducing a G1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions. CONCLUSIONS:
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Authors | Ana S Martins, Carlos Mackintosh, David Herrero Martín, Maria Campos, Teresa Hernández, Jose-Luis Ordóñez, Enrique de Alava |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 11 Pt 1
Pg. 3532-40
(Jun 01 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 16740780
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzamides
- Piperazines
- Pyrimidines
- Pyrroles
- Vincristine
- Doxorubicin
- Imatinib Mesylate
- Protein Kinases
- MTOR protein, human
- Receptor, IGF Type 1
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- NVP ADW742
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Topics |
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Apoptosis
(drug effects)
- Benzamides
- Bone Neoplasms
(drug therapy, metabolism)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Dose-Response Relationship, Drug
- Down-Regulation
(drug effects)
- Doxorubicin
(administration & dosage)
- Drug Screening Assays, Antitumor
- G1 Phase
(drug effects)
- Humans
- Imatinib Mesylate
- Phosphorylation
(drug effects)
- Piperazines
(administration & dosage)
- Protein Kinases
(drug effects, metabolism)
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors, metabolism)
- Pyrimidines
(administration & dosage, pharmacology, therapeutic use)
- Pyrroles
(pharmacology, therapeutic use)
- Receptor, IGF Type 1
(antagonists & inhibitors, metabolism)
- Sarcoma, Ewing
(drug therapy, metabolism)
- Structure-Activity Relationship
- TOR Serine-Threonine Kinases
- Vincristine
(administration & dosage)
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