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Development of COX inhibitors in cancer prevention and therapy

Gastrointestinal & Other Cancers Research Group, National Cancer Institute, Division of Cancer Prevention, Bethesda, Maryland 20892-7317, USA.
American journal of clinical oncology (Impact Factor: 2.61). 09/2003; 26(4):S48-57. DOI: 10.1097/01.COC.0000074157.28792.02
Source: PubMed

ABSTRACT On the strength of in vitro, in vivo, observational, and clinical data, nonsteroidal antiinflammatory drugs (NSAIDs)-also referred to as COX inhibitors-have emerged as lead compounds for cancer prevention, and possible adjuncts to cancer therapy. Thus far, the routine use of NSAIDs for these indications is limited, largely owing to toxicity concerns, the paucity of efficacy data for any specific target organ, and uncertainties with regard to the most appropriate regimen (i.e., the best agent, formulation, dose, route of administration, and duration). Strategies to address these concerns primarily aim to improve the therapeutic index (i.e., benefit:risk ratio) of COX inhibitors by 1) minimizing systemic exposures whenever feasible, 2) achieving greater mechanistic specificity, 3) coadministering agents that provide prophylaxis against common toxicities, and 4) coadministering other effective anticancer agents. Clinical trials testing most of these strategies have been completed or are under way. The National Cancer Institute has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs as preventive and therapeutic anticancer agents. Discovering how to apply NSAIDs in persons with-or at risk for-cancer, although challenging, has the potential for considerable clinical and public health benefits.

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    • "NSAIDs are important agents for cancer prevention and may serve as possible adjunct in cancer treatment based on reports that they stimulate anticancer effects in vitro, inhibit carcinogenesis in carcinogen-induced and genetically driven rodent models, reduce the incidence of colorectal precancerous lesions and colon cancer incidence, and regress precancerous lesions in genetic and sporadic cancer risk cohorts [8] [9] [10] [11] [12]. However, NSAID-induced upper gastrointestinal side effects remain a major problem that affects a broad segment of the population, due to frequent prescription and over the counter dispensing [13]. "
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    Biochemical pharmacology 12/2011; 83(6):723-32. DOI:10.1016/j.bcp.2011.12.019 · 4.65 Impact Factor
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    • "Several studies have also demonstrated that NSAIDs may be effective in the prevention and treatment of certain types of cancers [6] [7] [8] [9]. The chemopreventive and antitumorigenic effects of NSAIDs are believed to be exerted through the induction of apoptosis followed by inhibition of COX- 2 [10] [11] [12] [13]. "
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    ABSTRACT: We demonstrated that hydrophobic derivatives of the nonsteroidal anti-inflammatory drug (NSAID)flufenamic acid (FA), can be formed into stable nanometer-sized prodrugs (nanoprodrugs) that inhibit the growth of glioma cells, suggesting their potential application as anticancer agent. We synthesized highly hydrophobic monomeric and dimeric prodrugs of FA via esterification and prepared nanoprodrugs using spontaneous emulsification mechanism. The nanoprodrugs were in the size range of 120 to 140 nm and physicochemically stable upon long-term storage as aqueous suspension, which is attributed to the strong hydrophobic interaction between prodrug molecules. Importantly, despite the highly hydrophobic nature and water insolubility, nanoprodrugs could be readily activated into the parent drug by porcine liver esterase, presenting a potential new strategy for novel NSAID prodrug design. The nanoprodrug inhibited the growth of U87-MG glioma cells with IC(50) of 20 μM, whereas FA showed IC(50) of 100 μM, suggesting that more efficient drug delivery was achieved with nanoprodrugs.
    04/2011; 2011:980720. DOI:10.1155/2011/980720
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    • "On one hand, specific COX-2 inhibitors were designed and ignited a lot of enthusiasm as nonsteroidal anti-inflammatory agents that would preserve gastric mucosa. Indications for such inhibitors included not only treatment of chronic inflammatory disorders such as osteoarthritis, acute pain, rheumatoid arthritis (Matheson and Figgitt 2001), and dysmenorrhea (Harel 2004) but also treatment and prevention of cancer (Umar et al. 2003; Arber 2008) and a potential effect in psychiatric disorders (Müller, Riedel, and Schwarz 2004). On the other hand, cardiac researchers headed by Bolli (2007) have shown that cardiac COX-2 is cardioprotective and an obligatory mediator of late ischemic preconditioning, so that COX-2 inhibition by either NS-398 or celecoxib abolishes preconditioning-induced cardioprotection (Shinmura et al. 2000). "
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