Tumor Immunology and Immunotherapy Laboratory Inserm U866, University of Burgundy, Dijon, France.
Adv Exp Med Biol. 2010;667:69-80. doi: 10.1007/978-1-4419-1603-7_7.
The lipid A analogs used in preclinical studies and clinical trials are not naturally-occurring forms of lipid A; they are synthetic molecules produced to be less toxic than lipid A itself and they do not reproduce the effects of natural lipid A molecules especially in vivo. The responses induced by lipid A analogs are summarized in this chapter: their fate in the blood stream and their toxicity as well as the lipid A tolerance and the tumor immune responses they induce. Lipid A is not found in the mammalian organism under normal circumstances so its use in cancer therapy raises important questions as to its different effects in vivo and its toxicity, particularly in cancer patients. Lipid A has to be injected intravenously (i.v.) to study its effects. Injections of chemically synthesized lipid A in humans and in animals produce sepsis symptoms, such as tachycardia, tachypnea, hyper or hypothermia and leukocytosis or leukopenia. Similar manifestations are observed after injection of purified lipopolysaccharide (LPS), which is why lipid A is usually thought of as the active part of LPS. While lipid A injection is therefore expected to induce reactions similar to septic shock, the lipid A molecules used to treat cancer are not natural forms but analogs, produced by chemical synthesis or genetic engineering, specifically selected for their low toxicity. The in vivo effects of such low-toxicity lipid A analogs are summarized in this chapter.
在临床前研究和临床试验中使用的脂质 A 类似物不是天然存在的脂质 A 形式；它们是合成分子，旨在降低毒性，并且不能复制天然脂质 A 分子的作用，特别是在体内。本章总结了脂质 A 类似物引起的反应：它们在血液中的命运及其毒性，以及脂质 A 耐受和它们诱导的肿瘤免疫反应。在正常情况下，哺乳动物体内不会发现脂质 A，因此在癌症治疗中使用脂质 A 引起了一些问题，例如其在体内的不同作用及其毒性，尤其是在癌症患者中。为了研究其作用，必须通过静脉内（i.v.）注射来使用脂质 A。在人和动物中注射化学合成的脂质 A 会产生败血症症状，如心动过速、呼吸急促、体温过高或过低以及白细胞增多或减少。在注射纯化的脂多糖（LPS）后也观察到类似的表现，这就是为什么脂质 A 通常被认为是 LPS 的活性部分。因此，尽管预期脂质 A 注射会引起类似于败血症性休克的反应，但用于治疗癌症的脂质 A 分子不是天然形式，而是类似物，通过化学合成或基因工程产生，专门选择其低毒性。本章总结了此类低毒性脂质 A 类似物的体内作用。
