NSAIDs and Colorectal Cancer Control: Promise and Challenges.

The chemoprevention of colorectal cancer (CRC) is a realistic option given the low acceptance and cost of screening colonoscopy. NSAIDs, currently not recommended for CRC prevention, are the most promising agents. Here, we review relevant work and assess the chemopreventive potential of NSAIDs. The chemopreventive efficacy of NSAIDs is established by epidemiological and interventional studies as well as analyses of cardiovascular-prevention randomized clinical trials. The modest chemopreventive efficacy of NSAIDs is compounded by their significant toxicity that can be cumulative. Efforts to overcome these limitations include the use of drug combinations; the emphasis on the early stages of colon carcinogenesis such as aberrant crypt foci, which may require shorter periods of drug administration; and the development of several families of chemically modified NSAIDs such as derivatives of sulindac, nitro-NSAIDs and phospho-NSAIDs, with some of them appearing to have higher safety and efficacy than conventional NSAIDs and thus to be better candidate agents. The successful development of NSAIDs as chemopreventive agents will likely require a combination of the following: identification of subjects at high risk and/or those most likely to benefit from chemoprevention; optimization of the timing, dose and duration of administration of the chemopreventive agent; novel NSAID derivatives and/or combinations of agents; and agents that may prevent other diseases in addition to CRC. Ultimately, the clinical implementation of NSAIDs for the prevention of CRC will depend on a strategy that drastically shifts the currently unacceptable risk/benefit ratio in favor of chemoprevention.

MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis.

Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-α, IFN-γ, IL-1ß, IL-6 and IL-10 by RT-PCR; prostaglandin E(2) (PGE(2)), cytoplasmic phospholipase A(2) (cPLA(2)) and myeloperoxidase by immunoassay; and COX-2 and NF- κB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A(2); reduced significantly the induced levels of TNF-α, IFN-γ, IL-1ß, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-κB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE(2) in the colon and PGE(2) metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-κB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-κB. MC-12 merits further development as an agent for the control of IBD.

Treatment and chemoprevention of NSAID-associated gastrointestinal complications.

The use of non-steroidal anti-inflammatory drugs has become ubiquitous worldwide and remains a common source of gastrointestinal morbidity. Antisecretory medications, particularly proton pump inhibitors, are effective in the treatment and prevention of NSAID-related gastrointestinal complications, including peptic ulcer disease and non-ulcer dyspepsia. A careful assessment of patients' risk factors for developing NSAID-related gastrointestinal complications should be undertaken prior to initiation of any NSAIDs. Patients who are considered at risk for developing gastrointestinal complications should receive concurrent antisecretory medical therapy to minimize the risk for GI complications.

Drug injury in the upper gastrointestinal tract: nonsteroidal anti-inflammatory drugs.

It is well established that nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin confer significant morbidity and mortality. The widespread use of these drugs has increased the absolute numbers of cases of NSAID- or aspirin-related upper gastrointestinal complications. Emerging data indicate that antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, may also increase risk for gastrointestinal bleeding. Multiple factors have been identified that increase risk for NSAID- and aspirin-related upper gastrointestinal complications. The highest risks are related to age (>60 years) and prior complicated peptic ulcer; additional risk factors include use of multiple NSAIDs and high doses of NSAIDS. Recent studies have demonstrated enhanced healing and prevention of NSAID- and aspirin-related gastrointestinal lesions with proton pump inhibitors.

NO-donating aspirin inhibits both the expression and catalytic activity of inducible nitric oxide synthase in HT-29 human colon cancer cells.

Nitric oxide-releasing aspirin (NO-ASA) is emerging as a potentially important chemopreventive agent against colon cancer. We examined in HT-29 human colon adenocarcinoma cells the effect of NO-ASA on the inducible form of nitric oxide synthase (NOS2), an enzyme implicated in colon carcinogenesis. NO-ASA inhibited in a time- and concentration-dependent manner the expression of NOS2 up to 70% compared to control (IC50 for this effect = 46 microM). NO-ASA also decreased the corresponding steady-state mRNA levels and this reduction preceded the reduction of protein levels by at least 6 h. NO-ASA also reduced the enzymatic activity of NOS2, as determined by a direct enzyme assay (maximal reduction = 80%) and by determining the accumulation of NO in the culture medium (IC50 for this effect = 36 microM). These effects of NO-ASA on NOS2 were paralleled by inhibition in cell growth (IC50 = 8.5 microM). These findings indicate that NO-ASA profoundly inhibits both the expression and enzymatic activity of NOS2 and suggest that these effects may represent an important mechanism for the colon cancer chemopreventive effect of NO-ASA.

Diagnosis and Treatment of Helicobacter pylori.

Helicobacter pylori infection remains a ubiquitous infection, especially in populations with poor socioeconomic conditions. Severe clinical outcomes of chronic infection include peptic ulcer disease and gastric cancer. Consensus meetings have developed guidelines for diagnosis, treatment, and management of H. pylori infection and related disorders in various populations. Clear benefits are obtained for H. pylori eradication in peptic ulcer disease and gastric mucosa-associated lymphoid tissue lymphoma. Most authorities agree that first-degree relatives of gastric cancer patients should undergo testing for H. pylori infection. H. pylori eradication in dyspepsia remains controversial. Global investigations continue to identify specific host and bacterial factors that are responsible for H. pylori-related inflammatory processes and development of clinical disease. Effective eradication regimens have been identified. The proton pump inhibitor (PPI)-based triple therapies are considered first-line therapy because of high patient compliance and good eradication rates. "Quadruple therapy" with bismuth-metronidazole-tetracycline plus a PPI is another first-line therapy with a similar eradication rate. This therapy is preferred in patients with penicillin allergy or prior exposure to clarithromycin. Rescue regimens are being developed because of rising antimicrobial resistance to metronidazole and clarithromycin in H. pylori strains. Emerging rescue combination therapies include furazolidone, rifabutin, and quinolones. These combination regimens are still preliminary and should be reserved for patients who have failed first-line therapies. Vaccine development remains elusive.

Hepatitis C knowledge among primary care residents: is our teaching adequate for the times?

BACKGROUND: Increasingly, primary care (PC) physicians will be the first to encounter patients with hepatitis C virus (HCV) infection. AIM: To determine opinions and practices of PC residents regarding HCV. METHODS: We administered a one-page questionnaire to 180 PC residents at five U.S. training programs. RESULTS: Respondents were distributed equally across postgraduate year, 83% were U.S. graduates, and 44% had seen >11 (HCV) patients in the past year. Residents tested for HCV in persons with: increased transaminases (83%), history of blood transfusion (46%), multiple tattoos (57%), +ANCA (16%), and alcohol abuse (31%). Sixteen percent of respondents tested all patients. Forty-one percent would vaccinate HCV patients for hepatitis A and 65% for hepatitis B while only 19% and 78% knew the respective vaccination schedules. Although no vaccine is available, 66% recommended vaccination for HCV. Only 37% and 29%, respectively, reported HCV genotype 1 as most common and most resistant to treatment. Fifty-three percent recommend liver biopsy before treating HCV. Only 52% reported alpha-interferon (IFN) with ribavirin as initial treatment for HCV while 28% recommend ribavirin or lamivudine alone or combinations of IFN and lamivudine or amantadine. As contraindications to treatment, 33% reported AIDS with PCP infection, 19% coronary artery disease, and 19% suicidal ideation. Sixty-nine percent felt that there was insufficient information on HCV. CONCLUSIONS: Many PC residents lack adequate knowledge of recommended guidelines for the management of HCV. Many test for HCV in inappropriate situations, are unclear regarding available vaccines and their administration, and are uncertain about current treatment. Education of PC residents on guidelines for detection and management of HCV must be improved.

Helicobacter pylori strain and the pattern of gastritis among first-degree relatives of patients with gastric carcinoma.

BACKGROUND: Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically-related strains of Helicobacter pylori or a common environment. METHODS: The pattern of gastritis and H. pylori from gastric cancer patients and their first-degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping. RESULTS: Sixteen index cases from Korea, the US, or Colombia and their 38 first-degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer. CONCLUSIONS: The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.

Genomic fingerprinting and genotyping of Helicobacter pylori strains from patients with duodenal ulcer or gastric cancer from different geographic regions.

Continuing attempts have been made to classify pathogenic strains within bacterial populations based on DNA fingerprints and to identify virulence factors in H. pylori. We studied 287 H. pylori isolates from patients with duodenal ulcer or gastric cancer from three different geographic regions. DNA fingerprints were generated using REP-PCR and analyzed by cluster analysis. The status of three candidate virulence factors-vacA polymorphism, cagA and iceA,-were examined by PCR amplification. Cluster analysis of the REP-PCR fingerprints showed clustering by geographic region but not by disease presentation. cagA was detected in 91.3% of the isolates. Differences in vacA subtypes were observed among the three geographic regions. There was no association between iceA subtypes and clinical outcome. We conclude that geographic differences among the H. pylori strains exist in single gene allelic variants as well as in the conserved noncoding regions such as REP sequences throughout the entire bacterial genome. We did not detect any association between disease presentation and H. pylori genotypes using either DNA fingerprinting or candidate single gene virulence factors.

Treatment and management of Helicobacter pylori infection.

Clinical and basic mechanisms of interaction between Helicobacter pylori and its host have been the subject of numerous publications in the past year. Two additional proton pump inhibitors (PPIs), esomeprazole and rabeprazole, have shown effectiveness in H. pylori eradication when combined with amoxicillin and clarithromycin, and esomeprazole has demonstrated its effectiveness with only one daily dose. Other important recent developments worldwide include evidence-based treatment guidelines established at a European consensus meeting, improved accuracy in the urea breath test and the stool antigen test, new recommendations for second-line therapy, and a greater understanding of antimicrobial resistance in treatment failure. In addition, new studies have confirmed that H. pylori infection and use of nonsteroidal anti-inflammatory drugs or aspirin are the major causes of peptic ulcer disease and ulcer bleeding. This paper reviews the results of these studies and their implications for future research.

H. pylori and gastric cancer: the Asian enigma.

The actual distribution of Helicobacter pylori infection and its related diseases in various Asian countries is controversial. Only limited information is available regarding this issue. We discuss the etiological role of H. pylori in gastric cancer through the Asian experience. Seroprevalence of H. pylori infection in asymptomatic subjects and the annual incidence rate of gastric cancer per 100,000 in various Asian countries are summarized from literature reviews and World Health Organization statistics, respectively. There is a large intercountry variation in incidence of gastric cancer and H. pylori seroprevalence among Asian countries. There is a strong link between H. pylori infection and gastric cancer in many countries, such as Japan. By contrast, the prevalence of H. pylori infection is high in some countries, including India and Bangladesh, but low gastric cancer rates have been reported. These disparate observations represent the Asian enigma. Factors that may influence the etiology of gastric cancer include the genetic diversity of the infecting H. pylori strains and differences in the host genetic background in various ethnic groups, including gastric acid secretion and genetic polymorphisms in proinflammatory cytokines. These factors, in addition to environmental factors, such as personal hygiene and dietary habits, reflect the multifactorial etiology of gastric cancer.