Nanus D M, Pfeffer L M, Bander N H, Bahri S, Albino A P
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Cancer Res. 1990 Jul 15;50(14):4190-4.
Human leukocyte alpha-interferon (IFN-alpha) has significant antitumor activity in advanced renal cell carcinoma (RC), with approximately 15% (range, 5 to 29%) of patients subjected to IFN-alpha therapy exhibiting a major objective response. We assayed 16 RC cell lines for intrinsic sensitivity to the growth-inhibitory effects of recombinant IFN-alpha. Similar to results observed in patients, cultured RCs could be divided into those that are inhibited by IFN-alpha and those that are not. In addition, the IFN-alpha-sensitive or -resistant phenotype of cultured RCs was correlated with surface expression of six unrelated kidney-associated differentiation antigens. The expression of one antigen, a Mr 160,000 glycoprotein (gp160), was found to correlate with resistance to IFN-alpha. Proliferation of seven RC cell lines expressing gp160 (gp160+) was not significantly inhibited by IFN-alpha at concentrations as high as 3000 units/ml. In contrast, proliferation of eight of nine RC cell lines lacking expression of gp160 (gp160-) was markedly inhibited by IFN-alpha. The effect of IFN-alpha on gp160+ and gp160- RC xenografts in nu/nu mice was examined. In separate experiments, two gp160+ RC cell lines and five gp160- RC cell lines were injected s.c. into nu/nu mice; one half of the mice were subsequently treated with 10(6) units of IFN-alpha i.p. 3 times a wk, and one half received no IFN-alpha. Tumors appeared at the sites of inoculation in all mice given injections of gp160+ RC cell lines within 10 to 25 days regardless of INF-alpha therapy. Mice given injections of gp160- RC cell lines, but not receiving IFN-alpha, also formed tumors. In contrast, gp160- RC cell lines injected into mice that were treated with IFN-alpha exhibited a marked sensitivity, as demonstrated by either no tumor formation or delayed tumor formation. We conclude that the absence of gp160 expression by RCs may be predictive of sensitivity to the antitumor effects of IFN-alpha and, thus, provide a basis for identifying IFN-responsive patients.
人白细胞α干扰素（IFN-α）对晚期肾细胞癌（RC）具有显著的抗肿瘤活性，接受IFN-α治疗的患者中约15%（范围为5%至29%）出现主要客观反应。我们检测了16种肾癌细胞系对重组IFN-α生长抑制作用的内在敏感性。与在患者中观察到的结果相似，培养的肾癌细胞可分为受IFN-α抑制的细胞系和不受抑制的细胞系。此外，培养的肾癌细胞对IFN-α敏感或耐药的表型与六种不相关的肾脏相关分化抗原的表面表达相关。发现一种抗原，即分子量为160,000的糖蛋白（gp160）的表达与对IFN-α的耐药性相关。七种表达gp160（gp160+）的肾癌细胞系在高达3000单位/毫升的IFN-α浓度下增殖未受到显著抑制。相比之下，九种缺乏gp160表达（gp160-）的肾癌细胞系中有八种的增殖受到IFN-α的显著抑制。研究了IFN-α对裸鼠中gp160+和gp160-肾癌细胞异种移植瘤的作用。在单独的实验中，将两种gp160+肾癌细胞系和五种gp160-肾癌细胞系皮下注射到裸鼠体内；随后，一半小鼠每周腹腔注射10^6单位IFN-α，共3次，另一半不接受IFN-α。无论是否接受IFN-α治疗，所有注射了gp160+肾癌细胞系的小鼠在10至25天内在接种部位都出现了肿瘤。注射了gp160-肾癌细胞系但未接受IFN-α的小鼠也形成了肿瘤。相比之下，注射到接受IFN-α治疗的小鼠体内的gp160-肾癌细胞系表现出明显的敏感性，表现为无肿瘤形成或肿瘤形成延迟。我们得出结论，肾癌细胞缺乏gp160表达可能预示着对IFN-α抗肿瘤作用的敏感性，从而为识别对IFN有反应的患者提供依据。
