Current status of colorectal cancer chemoprevention

Chemoprevention refers to suppression or reversal of the carcinogenic process using pharmacologic or nutritional agents. Colorectal carcinogenesis is a protracted, multistep process that offers opportunities for prevention. Aspirin and selective cyclooxygenase-2 inhibitors (coxibs) have been evaluated for the prevention of sporadic adenoma recurrence. Aspirin was shown to reduce adenoma recurrence rates in patients with prior colorectal neoplasms; however, the optimal dosage remains unclear. Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios. In this regard, nitric-oxide-releasing aspirin shows chemopreventive efficacy in preclinical models and holds promise for reduced toxicity in humans. Furthermore, ongoing chemoprevention trials are evaluating nutritional supplements, such as folic acid and selenium, and results are eagerly awaited.     

Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.