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Cytotoxic treatment selects for such up-regulation inasmuch as NF-\u03baB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-\u03baB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-\u03baB activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-\u03baB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-\u03baB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits I\u03ba kinase- \u03b2, a central mediator of NF-\u03ba activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with high-dose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicy-late or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo- or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-\u03ba activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-\u03ba antagonists and\/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angio-genesis by targeting cycling endothelial cells in tumors.<\/jats:p>","DOI":"10.1177\/1534735406291499","type":"journal-article","created":{"date-parts":[[2006,8,1]],"date-time":"2006-08-01T21:12:11Z","timestamp":1154466731000},"page":"252-268","source":"Crossref","is-referenced-by-count":65,"title":["Preadministration of High-Dose Salicylates, Suppressors of NF-\u03baB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy"],"prefix":"10.1177","volume":"5","author":[{"given":"Mark F.","family":"McCarty","sequence":"first","affiliation":[{"name":"Block Center for Integrative Cancer Care, Evanston, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith I.","family":"Block","sequence":"additional","affiliation":[{"name":"Block Center for Integrative Cancer Care, Evanston, 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