Insulin-like growth factor-I receptor antagonism results in increased cytotoxicity of breast cancer cells to doxorubicin and taxol.
Therapeutic strategies for patients with advanced-stage adenocarcinoma of the breast frequently include the use of cytotoxic chemotherapy. Insulin-like growth factor I (IGF-I) receptor, a key factor in cell-cycle regulation, is frequently overexpressed in high-grade breast cancers. IGF-I receptor overexpression in these tumors may provide a target for novel molecular therapy against this disease. Early passage samples of estrogen-responsive (ER+) MCF 7 and estrogen receptor-negative (ER-) MDA-231 cells were cultured in semi-confluent conditions. Dose-titrations were performed for doxorubicin and taxol with receptor modulation using IGF-I or a competitive receptor inhibitor, alphaIR3. The addition of 100 ng/ml IGF-I resulted in a >2-fold mitogenic response in both ER+ and ER- cells. Receptor activation prior to the treatment with cytotoxic chemotherapeutic agents altered the pattern of response with a 26.3% increase in IC50. Doxorubicin and taxol both produced dose-related toxicity with IC50 of 0.05 microg/ml and 0.00 microg/ml respectively. The addition of alphaIR3 resulted in increased cytotoxicity in IGF-I stimulated cells compared with the use of doxorubicin or taxol alone. These results suggest that IGF-I receptor modulation alters the response to cytotoxic chemotherapeutic agents in breast cancer cells.
Beech
D J
DJ
University of Tennessee-Memphis College of Medicine, Department of Surgery/Surgical Oncology, Memphis, TN 38163, USA. dbeech@utmem.edu
Parekh
N
N
Pang
Y
Y
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D017239:Paclitaxel / Q000633:toxicity*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D011960:Receptors, Estrogen / Q000032:analysis; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D017239:Paclitaxel