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From Molecular Analysis to Medical Practice: Recent Studies Reveal New Therapeutic Targets for an Old Medicine

1998; Wiley; Volume: 12; Issue: 12 Linguagem: Inglês

10.1096/fasebj.12.12.1061

1530-6860

Vincent Marchesi,

Cytokine Signaling Pathways and Interactions

Anyone who wonders whether basic research is really solving problems that affect the human population, or believes that the American public is not getting its money's worth in health care benefits, should take a look at the recent work on aspirin. Aspirin is a simple compound, consumed by hundreds of millions of people worldwide. It is estimated that 14 billion dollars were spent on aspirin related drugs last year. Referred to in the medical trade as a non-steroidal anti-inflammatory drug (NSAID), the aspirins collectively are the drug of choice for a wide range of symptoms, headache and joint pains, perhaps the two most common indications. Yet it now appears that individuals taking NSAIDs enjoy a 4050% reduction in colorectal cancer, in addition to the significant reduction in cardiovascular disease mortality that has been apparent for several years. But how could anyone call aspirin, a compound that was discovered by a chemist working for a German chemical company over a century ago, a triumph of modern basic research? The answer is described in lucid detail in a review on Cyclooxygenase in Biology and Disease that appears in this issue. Although it has been known since 1971 that the therapeutic effect of aspirin is related to its capacity to block the enzymatic conversion of arachadonic acid to one of several prostaglandins, only with the application of modern molecular approaches has it been possible to identify the specific enzymatic targets involved. Aspirin inhibits the actions of two different enzymes, referred to as COX-1 and COX-2, and these are distributed in different tissues throughout the body. The COX-1 enzyme appears to be responsible for generating prostaglandins that act “physiologically,” while COX-2 levels in different tissues can be increased following induction of the COX-2 gene by a large number of biological insults that result in inflammatory reactions. The latter can occur in any part of the body, including the central nervous system, possibly contributing to the pathogenesis of neuro-degenerative disorders of the Alzheimer's type. Because the COX-1 enzyme is needed for normal functions of the kidney and the stomach, its inhibition can result in serious damage to these organs. In addition to identifying the specific genes of each of the cyclooxygenases, modern molecular studies offer the prospect of developing a “better aspirin,” as pointed out in a recent Science article. By designing compounds that block COX-2 specifically and reversibly, it should be possible to create new aspirins that deal with pain and inflammation without damaging the kidney or the GI tract. Preliminary studies, based on the crystal structures of COX enzymes, suggest that it should be possible to create far more powerful and specific antiinflammatory agents. Comparable approaches to therapies for cardio-vascular disease, cancer and neurodegeneration will surely follow.