Synergistic interaction between an anti-p185HER-2 pseudomonas exotoxin fusion protein [scFv(FRP5)-ETA] and ionizing radiation for inhibiting growth of ovarian cancer cells that overexpress HER-2
Synergistic interaction between an anti-p185HER-2 pseudomonas exotoxin fusion protein [scFv(FRP5)-ETA] and ionizing radiation for inhibiting growth of ovarian cancer cells that overexpress HER-2
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DOI：
10.1006/gyno.2000.6040
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发表时间：
2001-02-01
影响因子：
4.7
通讯作者：
Bast, RC
中科院分区：
文献类型：
--
作者：
Schmidt, M;McWatters, A;Bast, RC
目标. HER-2原癌基因在15-30%的卵巢癌中过表达，为一部分患者提供了治疗靶点。我们先前描述了重组单链抗p185（HER-2）-假单胞菌外毒素A融合蛋白scFv（FRP 5）-ETA抑制培养中的癌细胞和体内肿瘤异种移植物生长的能力。我们还描述了抗p185（HER-2）-蓖麻毒素A链免疫毒素和电离辐射之间的协同相互作用，用于抑制过表达HER-2的卵巢癌和乳腺癌细胞的生长，我们在本报告中的目的是评估scFv（FRP 5）-ETA对已转染表达>10（6）p185（HER-2）的SKOv 3卵巢癌细胞的体外和体内作用受体/细胞（克隆-9002-18）。通过有限稀释分析在体外测量克隆形成生长的抑制。使用相同卵巢癌细胞系建立的异种移植物在体内测量肿瘤生长的抑制。克隆-9002-18细胞比亲本SKOv 3细胞对scFv（FRP 5）-ETA的细胞毒性作用显著更敏感。外毒素融合蛋白诱导克隆9002-18细胞凋亡，但不影响亲本SKOv 3细胞。用200-至2000-cGy外部束照射与scFv（FRP 5）-ETA组合处理克隆-9002-18细胞产生培养物中的克隆源性肿瘤细胞的协同消除。在体内，nu/nu小鼠皮下或腹腔内移植瘤的生长在用scFv（FRP 5）-ETA或I-131标记的-520 C9抗p185（HER-2）放射性核素缀合物处理10天后被显著抑制（P = 0.004），但联合处理没有观察到累加效应。ScFv（FRP 5）-ETA值得进一步评价用于过表达p185（HER-2）的卵巢癌的腹腔内治疗。(C)北京：科学出版社.
Objectives. The HER-2 proto-oncogene is overexpressed in 15-30% of ovarian cancers, providing a target for therapy in a fraction of patients. We previously described the ability of a recombinant single-chain anti-p185(HER-2)-Pseudomonas exotoxin A fusion protein, scFv(FRP5)-ETA, to inhibit growth of cancer cells in culture and tumor xenografts in vivo. We have also described synergistic interaction between an anti-p185(HER-2)-ricin A chain immunotoxin and ionizing radiation for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2, Our objective in this report was to evaluate the in vitro and in vivo effects of scFv(FRP5)-ETA against SKOv3 ovarian cancer cells that have been transfected to express >10(6) p185(HER-2) receptors per cell (clone-9002-18).Methods. Inhibition of clonogenic growth was measured in vitro by limiting dilution analysis. Inhibition of tumor growth was measured in vivo using heterografts established with the same ovarian cancer cell lines.Results. Clone-9002-18 cells were substantially more sensitive than parental SKOv3 cells to the cytotoxic effects of scFv(FRP5)-ETA. Exotoxin fusion protein induced apoptosis in clone-9002-18 cells, but did not affect parental SKOv3 cells. Treatment of clone-9002-18 cells with 200- to 2000-cGy external beam irradiation in combination with scFv(FRP5)-ETA produced synergistic elimination of clonogenic tumor cells in culture. In vivo, subcutaneous or intraperitoneal growth of tumor xenografts in nu/nu mice was significantly inhibited (P = 0.004) by treatment for 10 days with scFv(FRP5)-ETA or with I-131-labeled-520C9 anti-p185(HER-2) radionuclide conjugate, but additive effects were not observed with combined treatment.Conclusion. ScFv(FRP5)-ETA deserves further evaluation for intraperitoneal therapy of ovarian cancers that overexpress p185(HER-2). (C) 2001 Academic Press.