Radomski M W, Jenkins D C, Holmes L, Moncada S
Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Cancer Res. 1991 Nov 15;51(22):6073-8.
The existence and role of an L-arginine:nitric oxide (NO) pathway in two human colorectal adenocarcinoma cell lines, SW-480 and SW-620, were investigated. Both cell lines, which derive from the same patient, SW-480 from the primary tumor and SW-620 from its metastatic lesion, were shown to have a cytosolic, Ca(2+)-independent, NADPH-dependent NO synthase, the activity of which was lower in the cytosol of SW-620. These cells were more potent inducers of platelet aggregation. In contrast, SW-480, which had more NO synthase activity, were less potent inducers of platelet aggregation. Pretreatment of both cell lines with NG-monomethyl-L-arginine, an inhibitor of NO synthase, potentiated their proaggregating effect and made them equally active. Exogenous L-arginine, NO, and related nitrovasodilators all inhibited platelet aggregation induced by SW-620. The antiaggregating activity of NO was further potentiated by prostacyclin and by M&B22948, a selective inhibitor of cyclic GMP phosphodiesterase. We propose that the generation of NO by tumor cells inversely correlates with their metastatic potential. Furthermore, we show that the lower activity of NO synthase in metastatic cells is due to the presence in these cells of a low molecular weight inhibitor of the NO synthase. In addition, agents which modulate platelet function by a cyclic GMP-dependent mechanism may be useful in the prevention of tumor metastasis.
研究了L-精氨酸：一氧化氮（NO）途径在两种人结肠直肠腺癌细胞系SW-480和SW-620中的存在及作用。这两种细胞系均来源于同一患者，SW-480来自原发性肿瘤，SW-620来自其转移病灶，二者均显示具有一种胞质、不依赖Ca(2+)、依赖NADPH的NO合酶，其在SW-620细胞溶质中的活性较低。这些细胞是更强的血小板聚集诱导剂。相比之下，具有更高NO合酶活性的SW-480则是较弱的血小板聚集诱导剂。用NO合酶抑制剂NG-单甲基-L-精氨酸对两种细胞系进行预处理，增强了它们的促聚集作用，并使它们具有同等活性。外源性L-精氨酸、NO及相关硝基血管扩张剂均抑制SW-620诱导的血小板聚集。前列环素和环磷酸鸟苷磷酸二酯酶的选择性抑制剂M&B22948进一步增强了NO的抗聚集活性。我们提出肿瘤细胞产生NO的能力与其转移潜能呈负相关。此外，我们表明转移细胞中NO合酶活性较低是由于这些细胞中存在一种低分子量的NO合酶抑制剂。此外，通过环磷酸鸟苷依赖性机制调节血小板功能的药物可能有助于预防肿瘤转移。
