Redundancy of autocrine loops in human osteosarcoma cells

With the aim of identifying innovative therapeutic strategies for osteosarc oma patients who are refractory to conventional chemotherapy, we analyzed t he in vitro effects of the blockage of autocrine circuits. Since the insuli n-like growth factor-I receptor (IGF-IR)-mediated loop is relevant to the g rowth of osteosarcoma, we analyzed the activity of the ICF-IR-blocking anti body alpha IR3 in both sensitive and multidrug-resistant osteosarcoma cell lines. Only limited effects, however, were observed, suggesting the simulta neous existence of other autocrine circuits. Indeed, in a representative pa nel of 12 human osteosarcoma cell lines, in addition to the IGF-IR-mediated circuit, we demonstrated also a loop mediated by epidermal growth factor r eceptor as well as the presence of nerve growth factor, low-affinity nerve growth factor receptor as well as tyrosine receptor kinase A in the great m ajority of osteosarcomas. Therapies based on the inhibition of single circu its may have only limited effects in osteosarcoma, whereas the use of suram in, a drug which, besides other activities, non-selectively interferes with the binding of growth factors to their receptors, appears as a promising a lternative, in both sensitive and drug-resistant osteosarcoma cells. (C) 19 99 WiIey-Liss, Inc.