Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing's sarcoma cells.
Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing's sarcoma cells.
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发表时间：
2001-06
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通讯作者：
S. Benini;M. Manara;N. Baldini;V. Cerisano;M. Serra;M. Mercuri;P. Lollini;P. Nanni;P. Picci;K. Scotlandi
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作者：
S. Benini;M. Manara;N. Baldini;V. Cerisano;M. Serra;M. Mercuri;P. Lollini;P. Nanni;P. Picci;K. Scotlandi
尤文氏肉瘤 (ES) 需要创新的治疗方式，尽管采用了积极的多模式治疗方法，但这种肿瘤的存活率仍低得令人失望。我们和其他人（D. Yee 等人，J. Clin. Investig., 86: 1806-1814, 1990；K. Scotlandi 等人，Cancer Res., 56: 4570-4574, 1996）先前已证明由胰岛素样生长因子-I 受体 (IGF-IR) 介导的自分泌环路的存在及其发病相关性，这对于ES细胞在体外的存活和增殖。此外，我们报道了IGF-IR阻断单克隆抗体（MAb）αIR3以及苏拉明（一种通过与受体结合干扰生长因子的药物）抑制无胸腺小鼠ES细胞的致瘤和转移能力。在这项研究中，我们分析了能够阻断 IGF-IR 介导的环路的药物与传统细胞毒性药物的结合是否有价值，以设计更有效的治疗方案。 αIR3 MAb 和苏拉明治疗均显着增加了阿霉素和长春新碱这两种对 ES 具有主导作用的药物的体外抗肿瘤作用。这些发现是通过同时和序贯治疗获得的。对增殖率和凋亡的分析表明，αIR3 MAb和苏拉明显着增强了阿霉素诱导的G(1)期速率，而基本上不影响细胞周期的阿霉素-G(2)-M-阻断，并显着增加了细胞凋亡的诱导，这证实了IGF-IR的特异性阻断使ES细胞失去了预防药物诱导的细胞凋亡的重要工具。此外，多柔比星加αIR3 MAb的联合治疗显着增加了多柔比星诱导的ES细胞在软琼脂中形成集落的能力的损害。总之，我们表明，在 ES 中，通过中和性 MAb 或苏拉明阻断 IGF-IR 可能会大大增强常规化疗药物的抗肿瘤活性。
Innovative treatment modalities are needed for Ewing's sarcoma (ES), a neoplasm with a disappointingly low survival rate despite the use of aggressive multimodal therapeutic approaches. We and others (D. Yee et al., J. Clin. Investig., 86: 1806-1814, 1990; K. Scotlandi et al., Cancer Res., 56: 4570-4574, 1996) have previously shown the existence and the pathogenetic relevance of an autocrine loop, mediated by the insulin-like growth factor-I receptor (IGF-IR), which is crucial for survival and proliferation of ES cells in vitro. Moreover, we reported that the IGF-IR-blocking monoclonal antibody (MAb), alphaIR3, as well as suramin, a drug that can interfere with growth factor by binding to the receptors, inhibited both the tumorigenic and the metastatic ability of ES cells in athymic mice. In this study, we analyzed whether agents that can block the IGF-IR-mediated loop are of value in association with conventional cytotoxic drugs for the design of more effective therapeutic regimens. Both alphaIR3 MAb and suramin treatment significantly increased the antitumor in vitro effects of doxorubicin and vincristine, two drugs with a leader action on ES. These findings were obtained by both simultaneous and sequential treatments. Analysis of the proliferation rate and of apoptosis revealed that alphaIR3 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 increased the induction of apoptosis, which confirmed that the specific blockage of IGF-IR deprives ES cells of an important tool for the prevention of drug-induced apoptosis. Moreover, combination treatments of doxorubicin plus alphaIR3 MAb significantly increase the doxorubicin-induced impairment of the ability of ES cells to form colonies in soft agar. In conclusion, we showed that, in ES, the blockage of IGF-IR by a neutralizing MAb or by suramin may greatly potentiate the antitumor activity of conventional chemotherapeutic drugs.