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Treatment of cancer patients with lipid A analogs is now feasible. This is the culmination of a long story, beginning hundreds of years ago, of progress in different scientific fields bacteriology, chemistry, immunology, genetics, cell biology and experimental medicine. Knowing the history of this domain of research is important in understanding why there is increasing acceptance among the...
Lipid A is the lipophilic partial structure of bacterial lipopolysaccharide (LPS), which is a characteristic and essential component of the cell surface architecture of Gram negative bacteria. LPS constitutes the outer leaflet of the lipid bilayer of outer membrane which covers the outermost surface of bacterial cells. Structurally, LPS is composed of covalently bound three distinct parts,...
In recent years, lipid A as ‘endotoxic principle’ of bacterial lipopolysaccharide (LPS) and derivatives thereof have become increasingly important in the field of biomedical application such as for vaccination or as therapeutical, e. g., anti-tumor agent. For an understanding of these biological processes, however, a basic physicochemical characterization of lipid A and lipid A-like structures...
Entry of endotoxin (lipopolysaccharide (LPS) or lipid A) into the blood stream is causative for the emergence of sepsis and septic shock with all its pathophysiological consequences.1 Serum contains a whole variety of proteins that interact with endotoxin. As large as the number of different proteins interacting with endotoxin, as broad are the consequences of these interactions. Serum proteins...
The lipid A receptor consists of several subunits. Lipopolysaccharide binding protein (LBP) is a serum protein facilitating association of lipid A with CD14. The Lipid A-LBP-CD14 complex is further delivered to Toll-like receptor 4 (TLR4), which is essential for lipid A-mediated cellular activation. TLR4 associates with MD-2, which is required for surface expression and recognition of lipid...
Lipid A is a strong activator of monocytes to release immune stimulators such as proinflammatory cytokines. Overproduction of inflammatory cytokines such as TNF and IL-6 is known to cause septic shock that frequently leads to multiple organ failure and finally to death. In recent years, Lipid A has also been recognized by a Toll-like receptor, TLR4. Activation of TLR4by LPS or Lipid A triggers...
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...
The term “tolerance” from an immunological perspective, broadly encompasses a number of phenomena, but generally refers to a diminished responsiveness to LPS and/or other microbial products. With the discovery that many of the immunological, physiological and/or pathophysiological effects of LPS can be attributed to the lipid A moiety of the LPS molecule, a number of different lipid A analogs...
Studies in animal models showed that the antitumoral effect of LPS and of their biologically active moiety, lipid A, is indirect and relies on the induction of an immune response both innate and specific, leading to cytokine production. They also affect tumor development by inhibiting tumor blood flow and induce necrosis as well as apoptosis of tumor cells. Lipids A have been tested in animals,...
As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e. g., Melan-A/ MART-1, tyrosinase, gp 100)...
Cancer remains the second leading cause of death, after cardiovascular diseases, in industrialized countries. The first goal to achieveis to prevent cancer occurrence or to diagnose it at an early and curable stage. Some screening strategies have been developed, with controversies across countries, for several cancer type; colorectal, breasts or prostate cancer for example. Treatment...
One of the major advances in the treatment of cancer with lipid A is the possibility of chemically synthesizing, lipid A analogs that are both biologically active in cancer patients and very well tolerated. Biotechnological production of different lipid A forms is also possible but the chemical route is preferable as it avoids LPS contamination. This significant step was somewhat unexpected...
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