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Oxidants, antioxidants and the current incurability of metastatic cancers
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA
- e-mail: berejka{at}cshl.edu
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Abstract The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies. Also key to better understanding is why and how the anti-diabetic drug metformin (the world's most prescribed pharmaceutical product) preferentially kills oxidant-deficient mesenchymal p53− −cells. A much faster timetable should be adopted towards developing more new drugs effective against p53− − cancers.
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Although the mortality from many cancers, particularly those of haematopoietic cells, has been steadily falling, the more important statistic may be that so many epithelial cancers (carcinomas) and effectively all mesenchymal cancers (sarcomas) remain largely incurable. Even though an increasing variety of intelligently designed, gene-targeted drugs now are in clinical use, they generally only temporarily hold back the fatal ravages of major cancers such as those of the lung, colon and breast that have become metastatic and gone beyond the reach of the skilled surgeon or radiotherapist. Even though we will soon have comprehensive views of how most cancers arise and function at the genetic and biochemical level, their ‘curing’ seems now to many seasoned scientists an even more daunting objective than when the ‘War on Cancer’ was started by President Nixon in December 1971. Propelling me then, 40 years ago, to turn the Cold Spring Harbor Laboratory into a major site for unravelling the genetic underpinnings of cancer was the belief that once the gene-induced molecular pathways to cancer became known, medicinal chemists would go on to develop much more effective gene-targeted drugs. Unlike most early proponents of the ‘War on Cancer’, who thought that DNA-damaging chemotherapeutic agents would bring real victories in one to two decades, I thought three if not four more decades of focused research would need to pass before we would be in a position to go all out for total victory [ 1]. In fact, only after the 1988–2003 Human Genome Project provided the world with the highly accurate sequences for three billion human DNA letters has it been possible to begin to approach the true genetic complexity of cancer.
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© 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.
 Jim Watson's (JDW's) interest in cancer first publicly expressed itself through his teaching on tumour viruses after he joined the Harvard University Biology Department in the fall of 1956. Later, for the new Introductory Biology II, his last of 10 lectures focused on how cancer might be induced by DNA tumour viruses, the smallest of which probably only had DNA sufficient to code for 3–5 proteins. In his 1965 textbook, The Molecular Biology of the Gene, the last chapter (‘A geneticist's view of cancer’) raised the question of how a virus might have the capacity to turn on the cell cycle. Upon becoming director of the Cold Spring Harbor Laboratory in 1968, he changed its major research emphasis from microbial genetics to cancer (through recruiting Joe Sambrook from Renato Dulbecco's lab at the Salk Institute). Major among its early Cold Spring Harbor Laboratory eukaryotic accomplishments was the 1977 co-discovery of RNA splicing by Richard Roberts and Phil Sharp (MIT). JDW then necessarily devoted much of his time on scientific politics, first toward gaining National Institutes of Health (NIH) acceptance of the safety of recombinant DNA procedures (1973–1978), and second arguing for and then leading NIH's role in the Human Genome Project (1986–1992). In 2008, JDW's main interest moved to the curing of cancer focusing on the biochemistry of cancer cells as opposed to their genetic origins.
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