Orucevic A, Lala P K
Department of Surgery, University of Pittsburgh, Pennsylvania, USA.
Cancer Metastasis Rev. 1998 Mar;17(1):127-42. doi: 10.1023/a:1005969024182.
Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physiological and pathological processes including inflammation and cancer. Detrimental effects of excessive NO production during septic shock have been well recognized. We tested the hypothesis that 'capillary leak syndrome' following systemic interleukin-2 (IL-2) therapy resulted from a cascade of events leading to the induction of NO which, directly or indirectly, injured capillaries and caused fluid leakage. Our results provided the first direct evidence that the induction of active NO synthase (NOS) leading to the overproduction of NO is instrumental in IL-2-induced capillary leakage in mice and that successful blocking of this overproduction with chronic oral administration of NOS inhibitors can mitigate this leakage without interfering with the beneficial antitumor effects of IL-2 therapy. NO blocking agents can, in fact, improve IL-2-induced antitumor effector cell activation, as well as tumor regression. In our studies, NO blocking agents alone reduced the growth and metastasis of a murine mammary carcinoma, at least in part, by mitigating the invasion and angiogenesis-stimulating role of tumor-derived NO. Thus, NOS inhibitors may be useful in treating certain tumors and serve as valuable adjuncts to systemic IL-2 based immunotherapy of cancer and infectious diseases.
一氧化氮（NO）是一种强效的、寿命短暂且作用范围有限的生物活性分子，在包括炎症和癌症在内的生理和病理过程中发挥着关键作用。脓毒症休克期间过量产生NO的有害影响已得到充分认识。我们检验了以下假设：全身应用白细胞介素-2（IL-2）治疗后出现的“毛细血管渗漏综合征”是由一系列事件导致的，这些事件引发了NO的产生，NO直接或间接损伤毛细血管并导致液体渗漏。我们的结果提供了首个直接证据，即活性一氧化氮合酶（NOS）的诱导导致NO过量产生，这在IL-2诱导的小鼠毛细血管渗漏中起作用，并且通过长期口服NOS抑制剂成功阻断这种过量产生可以减轻这种渗漏，而不会干扰IL-2治疗的有益抗肿瘤作用。事实上，NO阻断剂可以改善IL-2诱导的抗肿瘤效应细胞活化以及肿瘤消退。在我们的研究中，单独使用NO阻断剂至少部分地通过减轻肿瘤源性NO的侵袭和促血管生成作用，降低了小鼠乳腺癌的生长和转移。因此，NOS抑制剂可能对治疗某些肿瘤有用，并可作为基于全身性IL-2的癌症和传染病免疫疗法的有价值辅助药物。
