Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.
Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.
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用抗肿瘤剂5,6-二甲基二苯甲酮-4-乙酸的小鼠中肿瘤中一氧化氮合酶的持续诱导。
DOI：
10.1038/bjc.1998.68
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发表时间：
1998
影响因子：
8.8
通讯作者：
Moncada, S
中科院分区：
文献类型：
--
作者：
Moilanen, E;Thomsen, LL;Miles, DW;Happerfield, L;Knowles, RG;Moncada, S
抗肿瘤药物5，6-二甲基黄原酮-4-乙酸(5，6-MeXAA)可诱导荷瘤B6D2F1小鼠肿瘤、脾、胸腺和小肠组织中一氧化氮合酶(NOS)的表达，但对肺、肝、肾、心脏和骨骼肌无明显影响。这种诱导模式不同于内毒素、胞壁二肽或短小棒状杆菌等因素引起的诱导模式。肿瘤组织中诱导型一氧化氮合酶(INOS)的诱导持续时间较长(3d达高峰)，而在其他组织中(12h达高峰)。免疫组织化学染色显示，iNOS定位于肿瘤内及周围的巨噬细胞和内皮细胞。5，6-MeXAA处理后血浆亚硝酸盐和硝酸盐(NOx)浓度也显著升高，在5，6-MeXAA处理后8-12小时达到峰值。一氧化氮合酶抑制剂L-鸟氨酸(NIO-NIO)可阻止血浆NO_x的增加，表明这是由于促进了NO的产生。荷瘤小鼠对5，6-MeXAA的反应比对照组更快，无论是在他们的血浆NOx增加方面，还是在他们较低的最大耐受剂量方面。L-NIO在显著抑制血浆NOx升高的剂量下，不能阻止5，6-MeXAA所致的肿瘤完全坏死和消退。总之，实验性抗肿瘤药物5，6-MeXAA诱导肿瘤相关巨噬细胞和免疫活性组织合成NO的作用与其对肿瘤生长的影响是平行的。然而，使用非选择性一氧化氮合酶抑制剂L-NIO的实验表明，在5，6-MeXAA在这一特定模型中的抗肿瘤作用机制中，NO不是一个重要的成分。
An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours. This pattern of induction is distinct from that caused by agents such as endotoxin, muramyl dipeptide or Corynebacterium parvum. The induction of NOS (iNOS) in the tumour was more persistent (maximal at 3 days) than in other tissues (maximal at 12 h). Immunohistochemical staining suggested that iNOS was located in macrophages and endothelial cells within and around the tumour. Treatment with 5,6-MeXAA also caused substantial increases in plasma nitrite and nitrate (NOx) concentrations that peaked at 8-12 h after 5,6-MeXAA. The increase in plasma NOx was prevented by a NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), indicating that it was due to enhanced production of NO. Tumour-bearing mice were more responsive than controls to 5,6-MeXAA both in their plasma NOx increase and in their lower maximally tolerated dose. L-NIO was unable to prevent the complete tumour necrosis and regression caused by 5,6-MeXAA at a dose that substantially inhibited the increase of plasma NOx. In conclusion, the experimental anti-tumour agent 5,6-MeXAA induced NO synthesis in tumour-associated macrophages and in immunologically active tissues in parallel with its effects on tumour growth. The experiments with a non-selective NOS inhibitor L-NIO, however, suggest that NO is not a significant component in the mechanism of the anti-tumour action of 5,6-MeXAA in this particular model.
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影响因子：
8.8
作者：
Thomsen, L L;Baguley, B C;Rustin, G J;O'Reilly, S M
通讯作者：
O'Reilly, S M
影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
DOI：
10.1073/pnas.92.10.4392
发表时间：
1995-05-09
影响因子：
11.1
作者：
JENKINS, DC;CHARLES, IG;MONCADA, S
通讯作者：
MONCADA, S
影响因子：
56.9
作者：
HIBBS, JB;TAINTOR, RR;VAVRIN, Z
通讯作者：
VAVRIN, Z
影响因子：
3.3
作者：
KILBOURN, RG;OWENSCHAUB, LB;GRIFFITH, OW
通讯作者：
GRIFFITH, OW