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Insulin-like growth factor receptor I targeting in epithelial ovarian cancer.
Gynecol Oncol. 2006 Feb; 100(2):389-96.GO

Abstract

OBJECTIVES

Preclinical evaluation of the anti-neoplastic activity of an insulin-like growth factor I receptor (IGF-IR) kinase inhibitor in ovarian cancer.

METHODS

The OVCAR-3 and OVCAR-4 cell lines were investigated under serum-free tissue culture conditions. IGF-I and IGF-II production were evaluated by standard ELISA and immunohistochemistry. IGF-IR expression and protein levels were evaluated by Western blotting. Cytotoxicity assays were performed in triplicates using the Alamar colorimetric assay. Apoptosis was evaluated by flow cytometry and by Western blotting for PARP.

RESULTS

The OVCAR-3 and OVCAR-4 cell lines produce IGF-I and IGF-II, and express IGF-IR, detectable by Western blotting, supporting the existence of an autocrine loop. The existence of this loop justified studies of NVP-AEW541, a small molecular weight inhibitor of the IGF-IR kinase. We observed growth inhibition of the ovarian cancer cell lines, with IC50 between 5 and 15 microM. We also observed that NVP-AEW541 sensitized cells to cisplatin in vitro. Western blotting demonstrated that NVP-AEW541 induced apoptosis at the concentrations that were used in the cytotoxicity assays, and decreased the concentration of the phosphorylated AKT signaling protein downstream of the IGF-IR.

CONCLUSIONS

IGF-IR is a potential new molecular target in ovarian cancer. The anti-neoplastic activity of NVP-AEW541 in ovarian cancer was observed at concentrations higher than those previously reported for multiple myeloma, suggesting the possibility that a portion of the observed anti-neoplastic activity could involve targets other than the IGF-IR. Experiments are being conducted to investigate the cytotoxicity profile in vivo and the clinical relevance of NVP-AEW541 in ovarian cancer treatment.

Authors+Show Affiliations

Division of Gynecologic Oncology, McGill University, Montreal, Quebec, Canada. walter.gotlieb@mcgill.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16300820

Citation

Gotlieb, Walter H., et al. "Insulin-like Growth Factor Receptor I Targeting in Epithelial Ovarian Cancer." Gynecologic Oncology, vol. 100, no. 2, 2006, pp. 389-96.
Gotlieb WH, Bruchim I, Gu J, et al. Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. Gynecol Oncol. 2006;100(2):389-96.
Gotlieb, W. H., Bruchim, I., Gu, J., Shi, Y., Camirand, A., Blouin, M. J., Zhao, Y., & Pollak, M. N. (2006). Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. Gynecologic Oncology, 100(2), 389-96.
Gotlieb WH, et al. Insulin-like Growth Factor Receptor I Targeting in Epithelial Ovarian Cancer. Gynecol Oncol. 2006;100(2):389-96. PubMed PMID: 16300820.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. AU - Gotlieb,Walter H, AU - Bruchim,Ilan, AU - Gu,Jing, AU - Shi,Ying, AU - Camirand,Anne, AU - Blouin,Marie-José, AU - Zhao,Yunhua, AU - Pollak,Michael N, Y1 - 2005/11/21/ PY - 2005/03/27/received PY - 2005/09/21/revised PY - 2005/09/22/accepted PY - 2005/11/23/pubmed PY - 2006/3/8/medline PY - 2005/11/23/entrez SP - 389 EP - 96 JF - Gynecologic oncology JO - Gynecol Oncol VL - 100 IS - 2 N2 - OBJECTIVES: Preclinical evaluation of the anti-neoplastic activity of an insulin-like growth factor I receptor (IGF-IR) kinase inhibitor in ovarian cancer. METHODS: The OVCAR-3 and OVCAR-4 cell lines were investigated under serum-free tissue culture conditions. IGF-I and IGF-II production were evaluated by standard ELISA and immunohistochemistry. IGF-IR expression and protein levels were evaluated by Western blotting. Cytotoxicity assays were performed in triplicates using the Alamar colorimetric assay. Apoptosis was evaluated by flow cytometry and by Western blotting for PARP. RESULTS: The OVCAR-3 and OVCAR-4 cell lines produce IGF-I and IGF-II, and express IGF-IR, detectable by Western blotting, supporting the existence of an autocrine loop. The existence of this loop justified studies of NVP-AEW541, a small molecular weight inhibitor of the IGF-IR kinase. We observed growth inhibition of the ovarian cancer cell lines, with IC50 between 5 and 15 microM. We also observed that NVP-AEW541 sensitized cells to cisplatin in vitro. Western blotting demonstrated that NVP-AEW541 induced apoptosis at the concentrations that were used in the cytotoxicity assays, and decreased the concentration of the phosphorylated AKT signaling protein downstream of the IGF-IR. CONCLUSIONS: IGF-IR is a potential new molecular target in ovarian cancer. The anti-neoplastic activity of NVP-AEW541 in ovarian cancer was observed at concentrations higher than those previously reported for multiple myeloma, suggesting the possibility that a portion of the observed anti-neoplastic activity could involve targets other than the IGF-IR. Experiments are being conducted to investigate the cytotoxicity profile in vivo and the clinical relevance of NVP-AEW541 in ovarian cancer treatment. SN - 0090-8258 UR - https://www.unboundmedicine.com/medline/citation/16300820/Insulin_like_growth_factor_receptor_I_targeting_in_epithelial_ovarian_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(05)00836-X DB - PRIME DP - Unbound Medicine ER -