1/3/2003 Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells Document title Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells Author(s) BEECH Derrick J. , PERER Elise, HELMS Jody, GRATZER Allison, NAN DENG Author(s) Affiliation(s) Department of Surgery/Section of Surgical Oncology, University of Tennessee-Memphis, College of Medicine, Memphis, TN, ETATS-UNIS Abstract More than 80% of patients with extremity sarcoma ultimately develop metastases to pulmonary sites. Doxorubicin alone or in combination with other chemotherapeutic agents may result in partial or complete tumor response for sarcoma pulmonary metastases. Regardless of the response, there has been no proven survival benefit from cytotoxic chemotherapy in the treatment of localized or metastatic soft tissue sarcoma. Insulin-like growth factor-I receptor (IGF-I-R) activation may contribute to resistance to chemotherapy in mesenchymal neoplasia. IGF-I-R activation by its ligand decreases in vitro cytotoxic response of sarcoma to doxorubicin, the most active agent against soft tissue sarcoma in adults. Furthermore, IGF-I-R is frequently overexpressed in soft tissue sarcoma and may predict poor response to traditional chemotherapy. The effect of doxorubicin on a human soft tissue sarcoma cell derived from a dedifferentiated lung metastasis was evaluated using titrated doxorubicin doses with and without exogenous IGF-I (100 ng/ml). Western blot analysis was performed to evaluate levels of phosphorylated IGF-I-R under control and experimental conditions. In vitro proliferation assays were performed. Nuclear activation through IGF-I receptor mediated pathways prior to exposing sarcoma cells to doxorubicin altered the pattern of response to doxorubicin with enhanced mitogenesis (>2-fold) and blunted doxorubicin cytotoxicity (>10% change in IC[50]). These data suggest that activation of IGF-I receptor in sarcoma cells is a potential mechanism for tumor resistance to doxorubicin. Inhibition of IGF-I receptor activation represents a novel approach to enhance the degree and duration of response to traditional chemotherapy against soft tissue sarcoma. Journal Title Oncology reports  (Oncol. rep.)  ISSN 1021-335X  Source 2003, vol. 10, no1, pp. 181-184 [4 page(s) (article)] (9 ref.) Language Anglais Publisher [S.n.], Athens, GRECE (1994) (Revue) English Keywords Cytokine ; Growth factor ; Malignant tumor ; Enzyme ; Isomerases ; Anthracyclins ; Human ; DNA topoisomerase (ATP-hydrolysing) ; Enzyme inhibitor ; Biological activity ; In vitro ; Treatment resistance ; Antineoplastic agent ; Antibiotic ; Doxorubicin ; Biological receptor ; Growth factor receptor ; Insulin like growth factor 1 ; Established cell line ; Soft tissue ; Sarcoma Location INIST-CNRS, Cote INIST : 26534, 35400010552215.0330 Copyright 2007 INIST-CNRS. All rights reserved No part of these records may be reproduced of distributed, in any form or by any means, without the prior written permission of INIST-CNRS. To view entire article, click here: http://cat.inist.fr/?aModele=afficheN&cpsidt=14036835