Drugs Emerging to Replace Aspirin and As Anti-Cancer Agents

7 October, 1998

Drugs Emerging to Replace Aspirin and As Anti-Cancer Agents

Aspirin is the only nonsteroidal anti-inflammatory drug that covalently modifies cyclooxygenases (Cox). Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2) that is induced for prostaglandin production to promote inflammation, pain and fevers, whereas its antithrombotic and ulcerogenic effects (side effects) result from its acetylation of COX-1 that is expressed constitutively and dominantly in normal tissues and important for the integrity of gut and kidney. Aspirin acetylates a serine residue in the arachidonic acid binding region (Ser530 of COX-1 and Ser516 of COX-2), thereby blocking the approach of the fatty acid substrate to the active site for its oxygenation. Although aspirin acetylates both isoforms of cyclooxygenase, it is 10ﾊto 100ﾊtimes as potent against COX-1 as against COX-2. Thus efforts have been made to synthesize compounds with enhanced Cox-2 selectivity. Varying the length of the acyl group attached to the salicylate moiety still retained Cox-1 selectivity.
Kalgutkar AS et al (1998: uid=9596581) now report the synthesis of (acetoxyphenyl)alkylsulfide pharmacophore, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), that is an acetoxy benzene substituted in the ortho position with an alkylsulfide, -S-CH2CC(CH2)3CH3, with strong selectivity for Cox-2. APHS was about 60ﾊtimes as potent as aspirin in enzyme inhibition and 21 times as selective for Cox-2 as for Cox-1. APSH acetylated Ser516 of Cox-2.

In biological assay systems, APHS inhibited RAW264.7 macrophage stimulated with LPS and IFNgamma to induce COX-2 (IC50 for PGD2 synthesis: 0.12 uM; that for aspirin: 100 uM). APSH also inhibited the growth of colon cancer cells, HCA-7, that constitutively overexpressed COX-2 (IC50: 2 uM), whereas HCT-15 cells that do not express COX-2 were insensitive. In fact, COX-2-selective inhibitor, SC-58125 (celecoxib, diarylheterocycle pharmacophore, from Monsanto) was recently shown to be a powerful inhibitor of colon carcinogenesis in nude mice implanted with transformed human colon cancer cell lines and induced by azoxymethane in Fischer rats (Sheng H et al. 1997: uid=97296215; Kawamori T et al. 1998: uid=9458081). Celecoxib was also fully as efficacious as NSAIDs for arthritis without any injury to the gut. Celecoxib and Merck's vioxx (that are well ahead on their way to the market) are non-covalently binding products to COX-2. It is now promising that APSH that covalently binds to the enzyme is comparable or superior in these activities.

As commented in this series of News and Commentaries (12 December, 1997), Makoto Taketo (U of Tokyo) and his coworkers found COX-2 expression in familial adenomatous polyposis (0.01% population). APC (adenomatous polyposis coli) of chromosome 5q21 is the causative gene for this genetic disease and also alleged to be related to sporadic colorectal, stomach and esophageal cancer. A knockout mouse of APC/del 716 (codon 716 deletion) died within 8 days when homozygous but survived and formed hundreds of polyps (in duodenum, jejunum and ileum rather than in colon) when heterozygous. The polyps formed as a monolayer under the normal layer of chorioepithelium thus the adenomatous tissue could be isolated in a pure form for analysis. Oshima M et al (1996: uid=97100981) measured COX-2 activities in polyps of different size formed in the APC/del knockout. COX-2 was found expressed already from early polyposis. When a double knockout (COX-2 gene Ptgs2:APC/del 716) was made, the number of polyps and their size decreased down to 15% in Pts2 (-/-). In addition, COX-2-selective inhibitor, MF-tricyclic (tricyclic methyl sulfone derivative), added in feed at 14 mg/kg, suppressed polyposis by 65%, whereas non-specific inhibitor, sulindac sulfide, showed only 25% suppression.

Recent epidemiological studies document a 40%-50% reduction in mortality from colorectal cancer in individuals taking NSAIDs (Smalley and DuBois, 1997: uid=97303809). Greater than 80% of colon cancers in humans have increased COX-2 levels when compared to adjacent normal tissue (Williams et al. 1997: uid=97467363) and as discussed above, COX inhibitors exhibit dramatic antineoplastic activity in a number of tumor model systems. It was suggested further that the antitumor effect of nonselective COX inhibitor, diclofenac, was due to an antiangiogenic effect (Seed MP et al. 1997: uid=98221936). In order to test the notion that COX is involved in angiogenesis, Tsuji M et al (1998: uid=98292170) cocultured endothelial cells and colon cancer cells (transfected COX-2-overexpressing Caco-2 cells or constitutively COX-2-expressing HCA-7 cells). These cancer cells produced high levels of angiogenic factors, which stimulated endothelial tube formation. In this system, a selective COX-2 inhibitor (NS-398) inhibited both the expression of angiogenic factors and endothelial tube formation (endothelial cell migration). In endothelial cells (HCT-116), where angiogenic factors are produced similarly to cancer cells (HCA-7), both a nonselective COX inhibitor (aspirin) and COX-1 antisense oligonucleotide inhibited endothelial tube formation, although a COX-2 selective inhibitor (NS-398) and COX-2 antisense oligonucleotide showed no inhibitory effect. Thus it seems that COX-2 regulates angiogenesis induced by colon cancer cells, whereas COX-1 regulates angiogenesis in endothelial cells. Antiangiogenesis is now considered to be a prime target against carcinogenesis. Anti-COX drugs may well emerge to be good candidates as specific agents against colon and other cancers.

COX-2 appears to be induced in several different pathophysiological conditions, namely oxidative stress, injury, inflammation, ischemia, seizures, neurodegenerative diseases and proliferative diseases. In addition to the use for inflammation and cancer, COX-2-selective inhibitors are now being tried for possible effects on Alzheimer's disease.

　

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