Leitão R F C, Ribeiro R A, Bellaguarda E A L, Macedo F D B, Silva L R, Oriá R B, Vale M L, Cunha F Q, Brito G A C
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina da Universidade Federal do Ceará, Rua Cel Nunes de Melo, 1127, 60.430-270 Fortaleza, CE, Brazil.
Cancer Chemother Pharmacol. 2007 Apr;59(5):603-12. doi: 10.1007/s00280-006-0301-y. Epub 2006 Aug 31.
Mucositis induced by antineoplastic drugs is an important, dose-limiting, and costly side effect of cancer therapy.
To investigate the role of nitric oxide (NO) on the pathogenesis of 5-fluorouracil (5-FU)-induced oral mucositis.
Oral mucositis was induced by two intraperitoneal (i.p) administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) in male hamsters. Animals were treated subcutaneously with saline (0.4 ml), 1,400 W (1 mg/kg), aminoguanidine (5 or 10 mg/kg) or Nphi-Nitro-L-Arginine Methyl Ester (L-NAME) (5, 10, or 20 mg/kg) 1 h before the injections of 5-FU and daily until sacrifice, on the tenth day. Macroscopic and histopathological analyses were evaluated and graded. Tissues from the cheek pouches were harvested for measurement of myeloperoxidase (MPO) activity, nitrite level, and immunohistochemistry for induced nitric oxide synthase (iNOS).
Treatment with 1,400 W or aminoguanidine reduced macroscopic and histological parameters of oral mucositis, and reduced the inflammatory cell infiltration as detected by histopathology and by MPO activity. In contrast, the administration of L-NAME did not significantly reverse the inflammatory alterations induced by experimental mucositis. Increased NOS activity, nitrite level and immunostaining for iNOS were detected on the check pouch tissue of animals submitted to 5-FU-induced oral mucositis on the tenth day.
These results suggest an important role of NO produced by iNOS in the pathogenesis of oral mucositis induced by 5-FU.
抗肿瘤药物引起的粘膜炎是癌症治疗中一种重要的、剂量限制性且代价高昂的副作用。
研究一氧化氮（NO）在5-氟尿嘧啶（5-FU）诱导的口腔粘膜炎发病机制中的作用。
在实验的第一天和第二天，通过两次腹腔注射5-FU（分别为60和40mg/kg）诱导雄性仓鼠发生口腔粘膜炎。在注射5-FU前1小时，给动物皮下注射生理盐水（0.4ml）、1,400W（1mg/kg）、氨基胍（5或10mg/kg）或Nω-硝基-L-精氨酸甲酯（L-NAME）（5、10或20mg/kg），并每天注射直至在第十天处死。对宏观和组织病理学分析进行评估和分级。采集颊囊组织用于测量髓过氧化物酶（MPO）活性、亚硝酸盐水平，并进行诱导型一氧化氮合酶（iNOS）的免疫组织化学检测。
用1,400W或氨基胍治疗可降低口腔粘膜炎的宏观和组织学参数，并减少组织病理学和MPO活性检测到的炎性细胞浸润。相比之下，给予L-NAME并没有显著逆转实验性粘膜炎诱导的炎性改变。在第十天，对接受5-FU诱导的口腔粘膜炎的动物的颊囊组织检测到NOS活性、亚硝酸盐水平增加以及iNOS免疫染色增强。
这些结果表明iNOS产生的NO在5-FU诱导的口腔粘膜炎发病机制中起重要作用。
