Fan Dominic, Yano Seiji, Shinohara Hisashi, Solorzano Carmen, Van Arsdall Melissa, Bucana Corazon D, Pathak Sen, Kruzel Ewa, Herbst Roy S, Onn Amir, Roach Jennifer S, Onda Masanori, Wang Qing-cheng, Pastan Ira, Fidler Isaiah J
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mol Cancer Ther. 2002 Jun;1(8):595-600.
Several tumors, including mesothelioma and ovarian cancer, can overexpress mesothelin, a glycosylphosphatidylinositol-linked differentiation glycoprotein. The membrane-bound type of mesothelin is found in the blood of cancer patients at a very low level, which makes mesothelin a good candidate for targeted therapy of certain cancers. An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM). Our studies in vitro showed that SS1(dsFv)-PE38 is significantly more cytotoxic to the high-mesothelin-producing NCI-H226 human non-small cell lung cancer cells than to human lung adenocarcinoma PC14PE6 cells, which do not express mesothelin. When administered at a nontoxic dose of 500 microg/kg on days 7, 9, and 11 to nude mice injected i.v. with the two human lung cancer cell lines, SS1(dsFv)-PE38 selectively inhibited experimental lung metastases produced by the mesothelin-producing NCI-H226 cells. Our data indicate that mesothelin-producing squamous cell carcinoma of the lung may be a good target for this immunotoxin.
包括间皮瘤和卵巢癌在内的几种肿瘤可过度表达间皮素，一种糖基磷脂酰肌醇连接的分化糖蛋白。在癌症患者血液中，膜结合型间皮素的水平非常低，这使得间皮素成为某些癌症靶向治疗的良好候选物。将抗间皮素二硫键连接的Fv（SS1 Fv）与铜绿假单胞菌外毒素A的截短突变体融合，以产生重组免疫毒素SS1（dsFv）-PE38，其对间皮素具有高结合亲和力（Kd = 0.7 nM）。我们的体外研究表明，与不表达间皮素的人肺腺癌PC14PE6细胞相比，SS1（dsFv）-PE38对高表达间皮素的NCI-H226人非小细胞肺癌细胞具有显著更高的细胞毒性。当在第7、9和11天以500μg/kg的无毒剂量静脉注射给接种了这两种人肺癌细胞系的裸鼠时，SS1（dsFv）-PE38选择性地抑制了由高表达间皮素的NCI-H226细胞产生的实验性肺转移。我们的数据表明，高表达间皮素的肺鳞状细胞癌可能是这种免疫毒素的良好靶点。
