Kohn E C, Sandeen M A, Liotta L A
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892.
Cancer Res. 1992 Jun 1;52(11):3208-12.
Aberrant signal transduction has been implicated in malignant transformation, growth, and progression. This has led to the proposal to use inhibitors of signal transduction pathways to treat cancer. One approach to circumventing potential toxicity and improving efficacy would be to target pathways upon which cancer cells selectively depend. Pathways associated with the malignant process involve calcium fluxes, the release of arachidonic acid, and the generation of phosphoinositides. In this report, CAI (L651582, NSC 609974), a substituted carboxyamido-imidazole and novel inhibitor of these selected signal transduction pathways, inhibits anchorage-dependent and -independent growth in a large series of human cancer cell lines. CAI pretreatment of HT-29 human colon cancer and 5R ras-transfected rat embryo fibroblast cells inhibits the formation and growth of experimental pulmonary metastases in nude mice. Oral administration of CAI in PEG-400 vehicle arrests growth and metastasis of transplanted human melanoma and ovarian cancer xenografts. No significant gross or histological toxicity was observed at CAI doses yielding blood levels in the concentration range demonstrated to inhibit select signal transduction pathways in vitro. These data indicate the feasibility and demonstrate a potential selectivity and sensitivity of using specific signal transduction inhibitors for the experimental treatment of cancer.
异常的信号转导与恶性转化、生长和进展有关。这导致了使用信号转导通路抑制剂来治疗癌症的提议。一种规避潜在毒性并提高疗效的方法是靶向癌细胞选择性依赖的通路。与恶性过程相关的通路涉及钙通量、花生四烯酸的释放以及磷酸肌醇的生成。在本报告中，CAI（L651582，NSC 609974），一种取代的羧酰胺基咪唑和这些选定信号转导通路的新型抑制剂，在一系列人类癌细胞系中抑制贴壁依赖性和非贴壁依赖性生长。对HT - 29人结肠癌细胞和5R ras转染的大鼠胚胎成纤维细胞进行CAI预处理可抑制裸鼠实验性肺转移的形成和生长。以PEG - 400载体口服给予CAI可阻止移植的人黑色素瘤和卵巢癌异种移植物的生长和转移。在产生的血药浓度范围能在体外抑制选定信号转导通路的CAI剂量下，未观察到明显的大体或组织学毒性。这些数据表明了使用特定信号转导抑制剂进行癌症实验治疗的可行性，并证明了其潜在的选择性和敏感性。
