Ueda H, Yamazaki M
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan.
J Immunother. 1997 Jan;20(1):65-9. doi: 10.1097/00002371-199701000-00007.
The effect of a novel synthetic lipid A analogue, ONO-4007, on tumor necrosis factor (TNF) production was investigated in normal and tumor-bearing mice. When vehicle was administered to normal mice, slight TNF activity was detected in some organs, but more TNF activity was detected in spleen, liver, lung, kidney, and serum when ONO-4007 (300 micrograms/mouse) was administered. When vehicle was given to tumor bearers, on the other hand, little TNF was detected in most organs, but when ONO-4007 was given, more TNF was produced in many organs, particularly spleen, liver, and tumor tissue. TNF production of spleen and liver reached a maximum 1-2 h after ONO-4007 injection and then decreased rapidly, but that of tumor remained high for at least 6 h after administration. When mice were pretreated with dexamethasone, TNF activity of normal organs were completely inhibited, but that of tumor was only partially decreased. We have shown that ONO-4007 causes rapid, definite growth inhibition of solid tumor, and speculate that long-sustained intratumoral TNF is the main cause of this beneficial anti-tumor effect. We report here that ONO-4007 can induce TNF in tumor locus, and its utilization may offer a new therapeutic method.
在正常小鼠和荷瘤小鼠中研究了新型合成类脂A类似物ONO - 4007对肿瘤坏死因子（TNF）产生的影响。给正常小鼠注射赋形剂时，在一些器官中检测到轻微的TNF活性，但当给予ONO - 4007（300微克/小鼠）时，在脾脏、肝脏、肺、肾脏和血清中检测到更多的TNF活性。另一方面，给荷瘤小鼠注射赋形剂时，在大多数器官中检测到很少的TNF，但给予ONO - 4007时，许多器官中产生了更多的TNF，特别是脾脏、肝脏和肿瘤组织。ONO - 4007注射后1 - 2小时，脾脏和肝脏的TNF产生达到最大值，然后迅速下降，但肿瘤组织中的TNF在给药后至少6小时仍保持高水平。当小鼠用地塞米松预处理时，正常器官的TNF活性被完全抑制，但肿瘤组织中的TNF活性仅部分降低。我们已经表明ONO - 4007能引起实体瘤快速、明确的生长抑制，并推测肿瘤内长期持续存在的TNF是这种有益抗肿瘤作用的主要原因。我们在此报告ONO - 4007可在肿瘤部位诱导TNF，其应用可能提供一种新的治疗方法。
