Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing's sarcoma cells

Innovative treatment modalities are needed for Ewing's sarcoma (ES), a neop lasm with a disappointingly low survival rate despite the use of aggressive multimodal therapeutic approaches. We and others (D, Yee et. ah, J. Clin, Investig., 86: 1806-1814, 1990; It. Scotlandi et al, Cancer Res., 56: 4570- 4574, 1996) have previously shown the existence and the pathogenetic releva nce of an autocrine loop, mediated by the insulin-like growth factor-I rece ptor (IGF-IR), which is crucial for survival and proliferation of ES cells in vitro, Moreover, we reported that the IGF-IR-blocking monoclonal antibod y (MAb), alpha IR3, as well as suramin, a drug that can interfere with grow th factor by binding to the receptors, inhibited both the tumorigenic and t he metastatic ability of ES cells in athymic mice. In this study, we analyz ed whether agents that can block the IGF-IR-mediated loop are of value in a ssociation with conventional cytotoxic drugs for the design of more effecti ve therapeutic regimens. Both alpha IRS MAb and suramin treatment significa ntly increased the antitumor irt vitro effects of doxorubicin and vincristi ne, two drugs with a leader action on ES. These findings were obtained by b oth simultaneous and sequential treatments. Analysis of the proliferation r ate and of apoptosis revealed that alpha IR3 MAb and suramin significantly enhanced the G(1)-phase rate induced by doxorubicin, without substantially affecting doxorubicin-G(2)-M-blockage of cell cycle, and significantly incr eased the induction of apoptosis, which confirmed that the specific blockag e of IGF-IR deprives ES cells of an important tool for the prevention of dr ug-induced apoptosis. Moreover, combination treatments of doxorubicin plus alpha IR3 MAb significantly increase the doxorubicin-induced impairment of the ability of ES cells to form colonies in soft agar, In conclusion, we sh owed that, in ES, the blockage of IGF-IR by a neutralizing MAb or by surami n may greatly potentiate the antitumor activity of conventional chemotherap eutic drugs.