BCOX2 Inhibition in Cancer Prevention

Since human colon cancers have elevated PGE2 levels compared to uninvolved mucosa (Bennett, Civier, Hensby, Melhuish, & Stamford, 1987 Rigas, Goldman, & Levine, 1993) and COX-2 is overexpressed in 45 of colon adenomas and 85 of colon carcinomas (Eberhart et al., 1994), it was proposed that inhibition of COX-2, the isoform overexpressed in cancer, would arrest carcinogenesis. Extensive preclinical data supported this approach. Multiple cell culture studies indicated the potential efficacy...

Inflammation and Its Connection to Neoplastic Progression

Inflammation as a fundamental response to injury has been recognized for many thousands of years. The Egyptians described abscesses and ulcers, and the Code of Hammurabi (2000 BC) detailed instructions on how to treat abscesses of the eye (Eisen, 1977). The Greek physician, Hippocrates may have been the first to regard inflammation as the beginning of a healing process, introducing words such as edema and erysipelas to describe its symptoms. The first comprehensive description of inflammatory...

No

SMC, smooth muscle cell EC, endothelial cell l- NAME, N -nitro-l-arginine methyl ester. Partially adapted from Wang (2002) and Fiorucci (2009). SMC, smooth muscle cell EC, endothelial cell l- NAME, N -nitro-l-arginine methyl ester. Partially adapted from Wang (2002) and Fiorucci (2009). FIGURE 8 Putative interaction of H2S and NO in vascular tissue. H2S may decrease the expression level of NOS, while NO may increase the expression of CSE. H2S may decrease the sensitivity of the cGMP pathways...

Translational Research

Translational research is generally viewed (Adams, 2008 Duyk, 2003 FitzGerald, 2005, 2007 LoRusso, 2009 Maienschein, Sunderland, Ankeny, & Robert, 2008 Wehling, 2008,2009 Woolf, 2008b) as a bench to bedside discipline designed to direct the findings of basic research to the production of new medications (Woolf, 2008b). Translational research may also be viewed as important in fulfilling the desire of basic scientists to have their work used for the benefit of mankind (Wehling, 2008) and to...

Chemokines and Cancer

Chemokines are a family of small (8-14 kDa) chemotactic cytokines comprising more than 46 members (Mackay, 2001). They are divided into four groups, C, CC, CXC, and CX3C, according to the number and spacing of the first two cysteine residues in the amino-terminal part of the protein. The CXC family can be further subdivided into two categories depending on the presence or absence of an ELR motif (glutamic acid-leucine-arginine) preceding the first cysteine residue in the protein (Strieter,...

C LT Receptor Blockers

LTs exert their action through two GPCR classes, BLT receptors activated by LTB4, and CysLT receptors activated by cysLTs (Brink et al., 2003). The BLT receptors are designated as BLT1 and BLT2, based on agonist affinity (Yokomizo, Izumi, & Shimizu, 2001). The receptors activated by cysLTs, CysLT1 and CysLT2, are characterized based on their sensitivity to antagonists developed for inhibition of LT-induced bronchoconstriction (Back, 2002). Inhibition of LT receptors can also attenuate the...

A LOX Inhibitors

Modulation of the various LOX isozymes may be of therapeutic value. Such approaches to chemoprevention may include inhibition of 5-LOX, FLAP, and 12-S-LOX activities or the use of LT receptor antagonists. Some of these agents are briefly discussed below. Early inhibitors of 5-LOX were nonselective antioxidants that had significant toxicity and lacked oral bioavailability (Kennedy, Chan, Ding, & Adrian, 2003). Zileuton, a specific 5-LOX inhibitor of N-hydroxyurea series (Carter et al., 1991),...

LOX Cascades

Lipoxygenases (LOXs) are a family of nonheme iron-containing dioxy-genases that are designated 5-, 8-, 12-, and 15-LOX, based on their regiospeci-ficity of interaction with arachidonic acid (Funk, 2001) (Fig. 3). LOX metabolite levels are elevated in various cancers, including colon, breast, prostate, lung, skin, and esophageal (Kashfi & Rigas, 2005). Some LOX products are procar-cinogenic, while others are anticarcinogenic (Shureiqi & Lippman, 2001). The procarcinogenic LOXs and...

Animal Models of Human Disease States

A major hurdle in the translational medicine undertaking is the fact that most preclinical animal models of disease generally lack predictive value with respect to the human condition under study. Indeed, the false positives that result from the present generation of animal assays are a major cause of NCE attrition in the clinic either because of lack of efficacy or the appearance of unacceptable side effects that were not detected preclinically. While there are notable, albeit retrospective,...

Biological Influence of the Spacer in NOASA

The defining entity in all NO-NSAIDs is NO. Structure-activity studies with NO-ASA indicated that NO was pivotal for its anticancer effects (Kashfi et al., 2005). However, careful reexamination regarding the contribution to the overall biological effect of each of the three structural components of NO-ASA in which the spacer joining the ASA to the NO-releasing moiety was aromatic, led to the surprising conclusion that the NO-releasing moiety was not required for the observed biological effects....