Chun M, Hoffmann M K
Cancer Res. 1987 Jan 1;47(1):115-8.
Bacterial lipopolysaccharide (LPS) induces the release of factors into the serum which enable mice to reject experimental tumors. One such factor is tumor necrosis factor which causes acute necrosis of syngeneic sarcoma transplants in mice. Effective therapeutic use of tumor necrosis factor is limited, however, by its toxicity. We show here that the efficacy of tumor necrosis factor can be substantially increased by combining its application with low doses of LPS. Our data suggest that LPS exerts its antitumor effects by engaging more than one defense mechanism. Characteristic for the activation of a biological system is a concomitant induction of negative feedback mechanisms which antagonize the initial stimulus. Interference with the negative feedback response may substantially increase biological reactions. We show here that the blocking of two negative feedback responses occurring as a consequence of treatment with LPS, namely the production of prostaglandin E and the generation of suppressor T-lymphocytes, increases dramatically the ability of mice to reject tumor transplants. Thus, through appropriate combination of different factors one may reduce the dose of each below toxic levels and through interference with negative feedback responses increase the efficacy of antitumor reagents. We consider our findings in the context of formulating an effective immunotherapy of malignancies and as a promising step toward it.
细菌脂多糖（LPS）可诱导多种因子释放到血清中，使小鼠能够排斥实验性肿瘤。其中一种因子是肿瘤坏死因子，它可导致小鼠体内同基因肉瘤移植瘤发生急性坏死。然而，肿瘤坏死因子的有效治疗应用因其毒性而受到限制。我们在此表明，将肿瘤坏死因子与低剂量LPS联合应用可显著提高其疗效。我们的数据表明，LPS通过激活多种防御机制发挥其抗肿瘤作用。生物系统激活的一个特征是伴随诱导负反馈机制，该机制会对抗初始刺激。干扰负反馈反应可能会大幅增强生物反应。我们在此表明，阻断因LPS治疗而产生的两种负反馈反应，即前列腺素E的产生和抑制性T淋巴细胞的生成，可显著增强小鼠排斥肿瘤移植瘤的能力。因此，通过适当组合不同因子，可以将每种因子的剂量降低到毒性水平以下，并通过干扰负反馈反应提高抗肿瘤试剂的疗效。我们从制定有效的恶性肿瘤免疫治疗方案的角度考虑我们的研究结果，并认为这是朝着该目标迈出的充满希望的一步。
