A novel design of targeted endocrine and cytokine therapy for breast cancer.
A novel design of targeted endocrine and cytokine therapy for breast cancer.
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发表时间：
2002-04
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通讯作者：
Guorong Zhang;Wei Li;L. Holle;Nian-yi Chen;Wen Chen
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作者：
Guorong Zhang;Wei Li;L. Holle;Nian-yi Chen;Wen Chen
本研究的目的是将内分泌治疗[人催乳素（hPRL）拮抗剂，G129R]和免疫治疗[白细胞介素2（IL2）]结合起来设计融合蛋白G129R-IL2来治疗人类乳腺癌。这种新方法利用 G129R 和 hPRL 受体 (PRLR) 之间的特异性相互作用，从而将融合蛋白直接靶向先前已被证明含有高水平 PRLR 的恶性乳腺组织。这种局部双功能融合蛋白旨在阻断 hPRL 诱导的信号转导，并激活肿瘤部位附近的 T 淋巴细胞。使用细菌表达系统产生 G129R-IL2 融合蛋白，该融合蛋白保持 G129R 和 IL2 活性，如信号转导子和转录激活子 (STAT)5 磷酸化、乳腺癌细胞增殖和 T 细胞增殖等基于细胞的测定所证明的。使用 BALB/c 小鼠和 EMT6-hPRLR 乳腺癌细胞的同基因模型系统在体内证明了 G129R-IL2 的抗肿瘤活性。每天注射（i.p.）G129R-IL2（100微克/小鼠）18天后，G129R-IL2治疗组的肿瘤生长大小仅为对照组的三分之一。 G129R-IL2治疗组的生长速度也明显慢于单独用G129R治疗的组（200微克/小鼠/天）。我们希望这种新型双功能蛋白将为人类乳腺癌的治疗做出重大贡献。
The aim of this study is to combine endocrine therapy [human prolactin (hPRL) antagonist, G129R] and immune therapy [interleukin 2 (IL2)] in the design of a fusion protein, G129R-IL2, to treat human breast cancer. This novel approach uses the specific interaction between the G129R and hPRL receptors (PRLRs), thus directly targeting the fusion protein to the malignant breast tissues that have previously been shown to contain high levels of PRLR. The localized bifunctional fusion protein is designed to block signal transduction induced by hPRL as well as to activate T lymphocytes near the tumor site. A bacterial expression system was used to produce G129R-IL2 fusion protein that maintained both G129R and IL2 activities as demonstrated by cell-based assays such as signal transducer(s) and activator(s) of transcription (STAT)5 phosphorylation, breast cancer cell proliferation, and T-cell proliferation. The antitumor activities of G129R-IL2 were demonstrated in vivo using a syngeneic model system with BALB/c mice and EMT6-hPRLR breast cancer cells. After daily injection (i.p.) of G129R-IL2 (100 microg/mouse) for 18 days, the tumor growth in the G129R-IL2-treated group was only one-third the size as compared with that of the control group. The growth rate in the G129R-IL2-treated group is also significantly slower than that of the group treated with G129R alone (200 microg/mouse/day). We hope that this novel bifunctional protein will contribute significantly to human breast cancer therapy.