Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice.
Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice.
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发表时间：
1998-03
期刊：
影响因子：
11.2
通讯作者：
Ramón Mangues;Teresa Corral;N. Kohl;W. Symmans;Suying Lu;Marcos Malumbres;J. Gibbs;A. Oliff;A. Pellicer
中科院分区：
文献类型：
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作者：
Ramón Mangues;Teresa Corral;N. Kohl;W. Symmans;Suying Lu;Marcos Malumbres;J. Gibbs;A. Oliff;A. Pellicer
我们测试了法尼基转移酶抑制剂L-744，832对转基因小鼠中过表达N-ras原癌基因的乳腺和淋巴肿瘤的抑制作用。将携带乳腺肿瘤的小鼠随机分配至每日接受40 mg/kg s.c.注射该化合物（实验组，n = 6）或载体（对照组，n = 6），持续5.5周。与对照组（+28.2mm3/天; P < 0.001）相比，用化合物治疗显著降低了实验组中的乳腺肿瘤平均生长速率（-0.7mm3/天）。治疗结束时淋巴瘤发生率实验组为0例，对照组为3例，两组比较差异有统计学意义（P < 0.05）。因此，该化合物可有效治疗体内乳腺癌和淋巴瘤，其中活化的N-Ras途径驱动肿瘤发生。实验组乳腺肿瘤中的凋亡数字（14.7 +/- 8.1）显著高于对照组（5.7 +/- 3.5）（P = 0.04），表明凋亡诱导可能有助于该化合物的抗肿瘤活性机制。我们分析了从用L-744，832或媒介物处理的乳腺肿瘤（在体内或体外（在相同肿瘤的原代培养后））和从几种体外处理的对照细胞系获得的蛋白质提取物的免疫沉淀和蛋白质印迹后N-Ras和H-Ras的加工水平。在所有化合物处理的乳腺肿瘤和细胞系中，H-Ras大部分是未加工的（在体外处理后比在体内处理后更是如此），而N-Ras大部分保持加工。H-Ras和N-Ras在所有媒介物处理的样品中保持完全加工。这些发现与在我们的N-ras模型中用该化合物治疗的较低强度的抑制作用相一致，该抑制作用比先前报道的相同化合物在H-ras转基因中的作用低。此外，在化合物治疗的乳腺肿瘤中，N-Ras蛋白主要保持加工的发现表明，在我们的模型中，除Ras外的其他蛋白质可能是化合物的靶点。我们的研究结果和先前在人类造血系统恶性肿瘤中频繁的N-ras激活的发现支持L-744，832在治疗具有激活的N-Ras通路的淋巴瘤和乳腺癌中的作用，以及在人体中检测法呢基蛋白转移酶抑制剂以确定其临床相关性。
We tested the antineoplastic effect of the farnesyltransferase inhibitor L-744,832 in mammary and lymphoid tumors overexpressing the N-ras proto-oncogene in transgenic mice. Mice bearing mammary tumors were randomly assigned to receive daily 40 mg/kg s.c. injections of this compound (experimental group, n = 6) or vehicle (control group, n = 6) per day for 5.5 weeks. Treatment with the compound significantly reduced the mammary tumor mean growth rate in the experimental group (-0.7 mm3/day), as compared with the control group (+28.2 mm3/day; P < 0.001). There was a significant difference in lymphoma incidence at the end of the treatment between the experimental (0 of 6) and the control (3 of 6) groups (P < 0.05). Therefore, this compound is effective in treating in vivo mammary carcinomas and lymphomas in which an activated N-Ras pathway drives tumorigenesis. The number of apoptotic figures in mammary tumors was significantly higher (P = 0.04) in the experimental (14.7 +/- 8.1) than it was in the control (5.7 +/- 3.5) group, indicating that apoptotic induction could contribute to the mechanism of antitumor activity of this compound. We analyzed the level of processing of N-Ras and H-Ras after immunoprecipitation and Western blotting of protein extracts obtained from mammary tumors treated with L-744,832 or vehicle, either in vivo or in vitro (after primary culture of the same tumors), and from several in vitro treated control cell lines. In all compound-treated mammary tumors and cell lines, H-Ras was mostly unprocessed (more so after in vitro than after in vivo treatment), whereas N-Ras remained mostly processed. Both H-Ras and N-Ras remained fully processed in all vehicle-treated samples. These findings are consistent with a less intense antineoplastic effect of the treatment with the compound in our N-ras model than the effect previously reported for the same compound in H-ras transgenics. In addition, the finding that, in compound-treated mammary tumors, the N-Ras protein remains mainly processed suggests that, in our model, other proteins in addition to Ras may be a target for the compound. Our results and the previous findings of frequent N-ras activation in human hematopoietic malignancies support a role for L-744,832 in the treatment of lymphomas and of mammary carcinomas with an activated N-Ras pathway, as well as the testing of a farnesyl protein transferase inhibitor in humans to establish its clinical relevance.