Prolactin antagonist-endostatin fusion protein as a targeted dual-functional therapeutic agent for breast cancer.
Prolactin antagonist-endostatin fusion protein as a targeted dual-functional therapeutic agent for breast cancer.
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发表时间：
2003-07
期刊：
影响因子：
11.2
通讯作者：
M. T. Beck;N. Chen;K. Franek;Wen Chen
中科院分区：
文献类型：
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作者：
M. T. Beck;N. Chen;K. Franek;Wen Chen
在以前的研究中（Chen，W. Y.例如，临床癌症研究，5：3583-3593，1999; Chen，NY.例如，国际肿瘤学杂志，20：813-818，2002），我们已经证明了人催乳素（hPRL）拮抗剂G129 R在体外抑制人乳腺癌细胞增殖和减缓小鼠中肿瘤生长速率的能力。G129 R抗肿瘤作用的机制可能是通过调控bcl-2基因表达诱导细胞凋亡。已经确定的是，为了维持肿瘤的生长，需要血管网络的发展来引入营养物质，这一过程称为血管生成。破坏血管生成已被证明是导致某些肿瘤消退的有效策略。研究最多的血管生成抑制剂之一是内皮抑制素，其通过抑制内皮细胞发挥作用。在这项研究中，我们联合收割机结合G129 R的抗乳腺肿瘤作用和内皮抑素的抗血管生成作用，通过创建一种新的融合蛋白（G129 R-内皮抑素），专门用于乳腺癌治疗。结果表明，该融合蛋白能与T-47 D人乳腺癌细胞上的PRL受体（PRLR）结合，抑制PRL诱导的信号转导。同时，G129 R-endostatin抑制人脐静脉内皮细胞（HUVEC）增殖，破坏内皮管结构的形成，其效力与endostatin相似。更重要的是，使用小鼠乳腺癌细胞系4 T1在体内证实了G129 R-内皮抑制素的治疗功效。与单独的G129 R或内皮抑制素相比，G129 R-内皮抑制素具有显著延长的血清半衰期，并且表现出比G129 R和内皮抑制素单独或组合更大的肿瘤抑制作用。综上所述，这些数据证明了G129 R-内皮抑素的双重治疗作用，并表明这种融合蛋白作为一种新的抗乳腺癌药物具有很大的前景。
In previous studies (Chen, W. Y. et al., Clin. Cancer Res., 5:3583-3593, 1999; Chen, N Y. et al., Int. J. Oncol., 20:813-818, 2002), we have demonstrated the ability of the human prolactin (hPRL) antagonist, G129R, to inhibit human breast cancer cell proliferation in vitro and to slow the growth rate of tumors in mice. We further revealed that the possible mechanisms of G129R antitumor effects act through the induction of apoptosis via the regulation of bcl-2 gene expression. It has been established that to sustain tumor growth, it is necessary for the development of a network of blood vessels to bring in nutrients, a process called angiogenesis. The disruption of angiogenesis has been proven to be an effective strategy to cause regression of certain tumors. One of the best-studied angiogenesis inhibitors is endostatin, which acts through the inhibition of endothelial cells. In this study, we combine the anti-breast tumor effects of G129R and the antiangiogenic effects of endostatin by creating a novel fusion protein (G129R-endostatin) specifically for breast cancer therapy. The data presented here demonstrated that this novel fusion protein was able to bind to the PRL receptor (PRLR) on T-47D human breast cancer cells and inhibit the signal transduction induced by PRL. At the same time, G129R-endostatin inhibited human umbilical vein endothelial cell (HUVEC) proliferation and disrupted the formation of endothelial tube structures with potency similar to that of endostatin. More importantly, the therapeutic efficacy of G129R-endostatin was confirmed using a mouse breast cancer cell line 4T1 in vivo. G129R-endostatin has a significantly prolonged serum half-life as compared with that of G129R or endostatin alone, and exhibited greater tumor inhibitory effects than G129R and endostatin individually or in combination. Taken together, these data demonstrate the dual therapeutic effects of G129R-endostatin, and suggests that this fusion protein has great promise as a novel anti-breast cancer agent.