From the New England Journal of Medicine, March 17, 2005
Peter Curtis-Prior's 57-chapter book took five years to prepare and contains contributions from 106 authors. Its length reflects how ubiquitous essential fatty acids and their metabolites are in human and animal tissues. The clinical implications of eicosanoids -- molecules derived from fatty acids -- are innumerable. Eicosanoids, the topic of this book, are autacoids -- short-lived, physiologically active endogenous substances that act locally in response to injury and then undergo rapid inactivation. Histamine, bradykinin, serotonin, and angiotensin are also autacoids. The word "autacoid" is derived from the Greek autos ("self") and akos ("medicinal agent" or "remedy"). All eicosanoids are biotransformation products of essential fatty acids. Humans must obtain linoleic and arachidonic acids through the diet, because the pathway of fatty acid synthesis ends with oleate. The arachidonate derived from linoleate is esterified to phospholipids in the cell membrane. On physical, chemical, or pharmacologic perturbation, cells release arachidonate from these phospholipids through the action of phospholipase A(sub 2). Free intracellular arachidonate is immediately metabolized by a cyclooxygenase (COX-1 or COX-2) and by one or more lipoxygenases or epoxygenases. The metabolites of the cyclooxygenase pathway include prostaglandins and, most important, prostacyclin and thromboxane. The lipoxygenases generate hydroxy fatty acids, leukotrienes, and lipoxins. Curtis-Prior's book points to many of the clinical implications of the biochemistry of eicosanoids. For example, the daily worldwide consumption of aspirin amounts to 70 tons. Aspirin irreversibly causes acetylation of a serine near the active site in both COX-1 and COX-2. In this way, COX-1 is inactivated, and prostaglandins, thromboxane, and prostacyclin are no longer synthesized. However, the formation of products of lipoxygenase continues. After the administration of aspirin, COX-2 is still partially active (its catalytic pocket allows "maneuvering room" and can contain arachidonic acid, even after acetylation). This process generates a new product, (15-R)-hydroxyeicosatetraenoic acid, leading to the formation of antiinflammatory, aspirin-triggered lipoxins. Research on eicosanoids has passed through three stages. The first was analytical: cells and tissues were directly analyzed for eicosanoid production. They were incubated with arachidonic acid or other intermediates, and the products were identified. During the writing of this review, the major pioneer in these endeavors, Dr. Sune Bergstrom, died. He and Drs. Bengt Samuelsson and Mats Hamberg set the standard for all subsequent eicosanoid research. The second stage was predominantly pharmacologic and physiological: cells and tissues were incubated with agonists or other cells to stimulate the tissue to contract, dilate, or secrete a new eicosanoid metabolite. This stage also involved platelet activation and recruitment, as well as chemotaxis and chemokinesis by leukotrienes. The "tissue cascades" developed by Sir John Robert Vane (who also died recently), Dr. Salvador Moncada, and Dr. Philip Needleman are prime examples of this stage. The third stage involved the biology of molecules and receptors. During this era, COX-2 and its specific inhibitors were discovered. A concept that is still evolving in regard to the role of COX-2 in the pathogenesis of certain cancers is highlighted in the timely chapter on eicosanoids and the pathogenesis of neoplastic diseases. This chapter reviews the role of COX-2 and derived eicosanoids in cell proliferation, apoptosis, modulation of the immune response, angiogenesis, and metastatic disease. The main focus is on data that suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the risk of cancer. We do not understand how locally secreted autacoids, with only a brief half-life, can exert a therapeutic effect on malignant cells (e.g., colon, head and neck, and bone metastases). For example, about 95 percent of infused prostaglandin E(sub 2) is metabolized during one passage through the pulmonary circulation. Is the action of NSAIDs in cancer due to an effect on classical eicosanoids, or are there pathways of essential fatty acid metabolism yet to be identified? As discussed in the articles by Solomon et al. and Bresalier et al. in this issue of the Journal, trials of COX-2 inhibitors as prophylaxis against colonic polyps and colon cancer have been suspended because of an increased incidence of cardiovascular events. An example is the Adenoma Prevention with Celecoxib trial. In this study, patients ingesting 400 mg of celecoxib daily had an increased risk of myocardial infarction and stroke in comparison with patients who received placebo. These complications are driven by activated platelets; celecoxib cancels the platelet-inhibiting action of prostacyclin. However, this action cannot be the only reason for an increased risk of vascular events among patients who took celecoxib, perhaps because many more patients in clinical trials involving more than 1000 subjects should have had a cerebrovascular event. An alternative explanation is that the affected patients represented a subgroup with a low threshold for platelet activation that surfaced only after at least 18 months of treatment with the COX-2 inhibitor. Testing of platelet function in at least a fraction of the patients, to measure dose responses to a variety of agonists, has not been performed in these or other pioneering studies such as the aspirin component of the Physicians' Health Study. Such testing might reveal subgroups of patients with symptoms that could be described as resistance to aspirin or COX-2 inhibitors. Investigators with either a basic or a clinical interest in the metabolism of essential fatty acids and eicosanoid production have all such information at hand in this excellent compendium. Aaron J. Marcus, M.D.Copyright © 2005 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
From Book News, Inc.
Curtis-Prior (Cambridge Research Institute) collects research on the derivatives of 20-carbon-atom fatty acids, known as the eicosanoids. Emphasis is on arachidonic acid and products formed by oxidation and further transformation. Researchers in cell biology, pharmacology, and various branches of medicine report on the latest eicosanoid research in biosynthesis, analytic methods, biochemical and molecular pharmacology, immunology, and the activity of eicosanoids in the circulatory, digestive, nervous, and reproductive systems. Specific topics examined include prostanoids in pain, biochemical interactions of platelet-activating factor with eicosanoids, time-resolved fluoroimmunoassay in eicosanoid analysis, mammalian lipoxygenases, and gas chromatography and mass spectrometry in eicosanoid analysis.Copyright © 2004 Book News, Inc., Portland, OR
Review
"Investigators with either or a basic or clinical interest in the metabolism of essential fatty acids and eicosanoid production have all such information at hand in this excellent compendium." (New England Journal of Medicine, March 17, 2005)
"…it serves to effectively communicate the most current information on eicosanoids in an understandable manner.” (E-STREAMS, September 2004)
Review
"Investigators with either or a basic or clinical interest in the metabolism of essential fatty acids and eicosanoid production have all such information at hand in this excellent compendium." (New England Journal of Medicine, March 17, 2005)
"…it serves to effectively communicate the most current information on eicosanoids in an understandable manner.” (E-STREAMS, September 2004)
Book Description
This comprehensive reference work, updated from the first edition, brings together the knowledge and expertise of contributors from around the world. It includes new topics such as prostaglandin synthetase enzyme, new synthetic eicosanoids, innovative analytical methods, the influence of cytokines in the regulation of synthesis and actions, newer eicosanoids that influence the cardiovascular system, and newly discovered roles in reproduction and interactions with nitric oxide.
This book satisfies a surge of interest in prostaglandins—NSAIDS (e.g. aspirin) are the biggest selling drugs of all time, and the field has been refreshed by the advent of new types (selective COX-2 inhibitors, anti-leukotiene drugs).
Download Description
"This comprehensive reference work, updated from the first edition, brings together the knowledge and expertise of contributors from around the world. It includes new topics such as prostaglandin synthetase enzyme, new synthetic eicosanoids, innovative analytical methods, the influence of cytokines in the regulation of synthesis and actions, newer eicosanoids that influence the cardiovascular system, and newly discovered roles in reproduction and interactions with nitric oxide.
This book satisfies a surge of interest in prostaglandins—NSAIDS (e.g. aspirin) are the biggest selling drugs of all time, and the field has been refreshed by the advent of new types (selective COX-2 inhibitors, anti-leukotiene drugs). "
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