Prewett M, Rothman M, Waksal H, Feldman M, Bander N H, Hicklin D J
Department of Immunology, ImClone Systems Incorporated, New York, New York 10014, USA.
Clin Cancer Res. 1998 Dec;4(12):2957-66.
The epidermal growth factor (EGF) receptor and its ligand transforming growth factor-alpha (TGF-alpha) are overexpressed in human renal cell carcinoma (RCC). The chimeric anti-EGF receptor monoclonal antibody C225 was used to determine the effects of blocking the EGF receptor on RCC growth both in vitro and in vivo. A panel of RCC cell lines all tested positive at various levels for EGF receptor cell surface expression. C225 inhibited DNA synthesis of cultured A498, Caki-1, SK-RC-4, SK-RC-29, and SW839 cells in a dose-dependent manner, ranging from 20 to 45% inhibition compared with untreated controls. C225 also inhibited exogenous ligand-stimulated tyrosine phosphorylation of EGF receptor on RCC cells. The antitumor effects of C225 on RCC tumor growth were evaluated in ascites, s.c., and orthotopic RCC xenograft models. Mice treated with C225 in a Caki-1 ascites xenograft model showed a significant increase in survival (P = 0.002). All control mice died with ascites tumors by week 9, whereas >70% of C225-treated mice survived beyond 12 weeks. C225 also inhibited the growth of s.c. SK-RC-29 tumors in a dose-dependent manner. Mice treated with C225 (1 mg/dose) displayed a significant decrease in tumor volume compared with mice treated with control antibody (P < 0.05) or vehicle alone (P < 0.01). Lastly, C225 inhibited the growth and metastasis of RCC tumors growing orthotopically in the renal subcapsule of nude mice. Histological examination of RCC tumors from mice treated with C225 showed a substantial decrease in proliferating cell nuclear antigen staining and an increase in tumor cell apoptosis. These data suggest that C225 affects growth of RCC tumors by inhibiting EGF receptor-dependent proliferation and demonstrate the potential for therapeutic application of C225 in the treatment of human renal cancer.
表皮生长因子（EGF）受体及其配体转化生长因子-α（TGF-α）在人类肾细胞癌（RCC）中过表达。嵌合抗EGF受体单克隆抗体C225被用于确定阻断EGF受体对RCC体外和体内生长的影响。一组RCC细胞系在不同水平上对EGF受体细胞表面表达均呈阳性。C225以剂量依赖方式抑制培养的A498、Caki-1、SK-RC-4、SK-RC-29和SW839细胞的DNA合成，与未处理的对照相比，抑制率在20%至45%之间。C225还抑制RCC细胞上外源性配体刺激的EGF受体酪氨酸磷酸化。在腹水、皮下和原位RCC异种移植模型中评估了C225对RCC肿瘤生长的抗肿瘤作用。在Caki-1腹水异种移植模型中用C225治疗的小鼠存活率显著提高（P = 0.002）。所有对照小鼠在第9周时死于腹水肿瘤，而超过70%接受C225治疗的小鼠存活超过12周。C225还以剂量依赖方式抑制皮下SK-RC-29肿瘤的生长。与用对照抗体治疗的小鼠（P < 0.05）或单独用赋形剂治疗的小鼠（P < 0.01）相比，用C225（1 mg/剂量）治疗的小鼠肿瘤体积显著减小。最后，C225抑制裸鼠肾被膜原位生长的RCC肿瘤的生长和转移。对用C225治疗的小鼠的RCC肿瘤进行组织学检查显示，增殖细胞核抗原染色显著减少，肿瘤细胞凋亡增加。这些数据表明C225通过抑制EGF受体依赖性增殖影响RCC肿瘤的生长，并证明了C225在治疗人类肾癌中的治疗应用潜力。
