Selective vitamin D receptor modulators and their effects on colorectal tumor growth.

The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is an endocrine hormone whose classic role is the maintenance of calcium homeostasis. It is well documented that 1,25(OH)(2)D(3) also has anti-tumor effects on a number of cancers and cancer cell lines including breast, colorectal, gastric, liver, ovarian, prostate, and non-melanoma skin cancers. Included in the anti-tumor activities of 1,25(OH)(2)D(3) are its ability to cause antiproliferation, prodifferentation and decrease angiogenesis. Furthermore, through regulation of the plaminogen activator (PA) system and a class of proteolytic enzymes called matrix metalloproteinases (MMPs), 1,25(OH)(2)D(3) reduces the invasive spread of tumor cells. Because of the calcemic limitations of using 1,25(OH)(2)D(3) as a therapy, we have tested the effects of a novel Gemini vitamin D analogue, Deuterated Gemini (DG), on mouse colorectal cancer. We demonstrated that DG is more potent in reducing tumor volume and mass, compared to control and 1,25(OH)(2)D(3). DG significantly prevented (100% reduction, p<0.05) the invasive spread of colorectal tumor cells into the surrounding muscle, and had no effect on serum calcium levels. Thus, DG acts as a selective vitamin D receptor modulator (SVDRM) by enhancing select anti-tumor characteristic 1,25(OH)(2)D(3) activities, without inducing hypercalcemia. Thus, DG shows promise in the development of colorectal cancer therapies.

Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs.

It has been recognized that people who live at higher latitudes and who are vitamin D deficient are at higher risk of dying from many common cancers including colon cancer. To evaluate the role of vitamin D deficiency on colon tumor growth, Balb/c adult male mice were fed either a vitamin D sufficient or vitamin D deficient diet for 10 weeks. Mice were arranged into groups of six and each animal received subcutaneously 10(4) MC-26 cells in the posterior trunk. The tumor size was recorded daily. By day 9 there was a significant difference in tumor volume between the vitamin D sufficient and vitamin D deficient mice. By day 18 the vitamin D deficient animals had a tumor size that was 56% larger compared to the animals that were vitamin D sufficient. To determine whether treatment with active vitamin D analogs could further decrease colon tumor growth in a vitamin D sufficient state, groups of mice were treated with the novel 19-nor-Gemini compounds. The mice were fed a low calcium diet. Twenty-four hours after tumor implantation, the mice received, three times weekly, one of the vitamin D analogs or the vehicle. The group that received Gemini 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-19-nor-20S-cholecalciferol (3) showed a dose-dependent decrease in tumor volume. On day 19, at the dose level of 0.02microg molar equivalents (E), the tumor volume was reduced by 41% when compared to the control group. At the same time point, the hexadeuterated analog 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-26,27-hexadeutero-19-nor-20S-cholecalciferol (4), administered at the 10-fold lower dose of 0.002microgE, showed a 52% reduction in tumor volume (p<0.05), compared to the control group. Animals that received 1,25(OH)(2)D(3) at 0.002 and 0.02microg showed a trend in tumor volume reduction at the highest dose but the changes were not statistically significant. An evaluation of serum calcium concentrations revealed that the calcium levels were normal in all groups, except the group receiving 0.02microgE of 4. The results from these studies demonstrate that vitamin D deficiency may accelerate colon cancer growth and that novel Gemini analogs of 1,25(OH)(2)D(3) may be an effective new approach for colon cancer treatment.

Non-steroidal anti-inflammatory drugs and colorectal cancer prevention.

Colorectal cancer is the second leading cause of cancer deaths in the United States. Currently, the most effective strategy available for colon cancer prevention is endoscopic screening, with polypectomy or surgical resection for advanced lesions. This intervention carries with it many concerns regarding cost, patient acceptance, and the growing burden of surveillance colonoscopies for patients with polyps. Further improvements in the understanding of the multistep model of colorectal carcinogenesis will probably lead to the development of other primary and secondary prevention strategies. Data obtained from animal and epidemiological studies and most recently from randomised, placebo controlled trials, suggest that non-steroidal anti-inflammatory drugs may prove effective chemopreventive agents in different groups of people, from patients with familial adenomatous polyposis to those with sporadic adenomas.

Review article: diagnosis and management of night-time reflux.

Symptoms of gastro-oesophageal reflux disease (GERD) range from mild to severe and, when they occur during night-time hours, can interfere with sleep patterns and reduce overall quality of life. The clinical presentation of GERD is characterized by oesophageal as well as supra-oesophageal symptoms, including otolaryngologic and pulmonary complications. However, GERD may be overlooked as the cause of a patient's supra-oesophageal symptoms because these complaints can occur in the absence of oesophageal symptoms or endoscopic changes. The role of available tools used for GERD diagnosis, including endoscopy, oesophageal pH monitoring and an empirical course of proton pump inhibitor therapy, is discussed. Interventions available to achieve the therapeutic goals of symptom relief and prevention include specific lifestyle modifications and over-the-counter as well as prescription pharmacological agents. Patient-initiated, as-needed treatment may not be the best choice for managing persistent night-time reflux because it requires patient arousal from sleep. Proton pump inhibitor therapy remains the treatment of choice for patients with more severe symptoms and those with erosive oesophagitis. Few studies have specifically evaluated the role of pharmacological agents in the management of night-time reflux and comparisons are difficult due to the variability in study design and endpoints assessed.

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC) by inhibiting the activity of cyclooxygenase (COX). The present studies were directed to determine whether selective COX-2 inhibition reduces CRC tumour cell proliferation and invasion/migration, and the possible cellular and molecular mechanisms involved. The MC-26 cells are a highly invasive mouse CRC cell line expressing COX-2 protein. NS-398 (100 microM), a highly selective COX-2 inhibitor, decreased cell proliferation by approximately 35% of control, as determined using [(3)H]-thymidine incorporation. This reduction in cell proliferation was associated with decreased expression of cyclin D1 and proliferating cell nuclear antigen (PCNA). Furthermore, NS-398 inhibited cell invasion/migration through Matrigel extracellular matrix components at 24 h by approximately 60%. The addition of exogenous prostaglandin E(2) partially attenuated the inhibition of cell invasion by 10 microM NS-398, but failed to reverse the effect of 100 microM NS-398. Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) are two enzymes that facilitate cell invasion/migration by degrading the extracellular matrix. In the presence of 100 microM NS-398, Western blot hybridisation analysis and zymography demonstrated that both MMP-2 and MMP-9 protein levels and enzyme activity were decreased by approximately 25-30%. In separate studies, NS-398 also inhibited tumour growth in vivo and retarded the formation of liver metastasis. The results of these studies indicate that the expression and activity of COX-2 appear to be associated with both the proliferative and invasive properties of CRC. Cyclooxygenase-2 inhibition suppresses tumour cell growth and invasion/migration, and retards liver metastasis in a mouse colon cancer model, via multiple cellular and molecular mechanisms.

The pharmacological management of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders, and the pharmacological management of GERD is a topic of intense interest given the sizeable yearly expenditure for antireflux therapies. GERD is primarily a motor disorder of the esophagus, yet pharmacological approaches directed at altering esophageal motility have been only partially effective. Antisecretory therapy is the mainstay of treatment for GERD. Both H2 receptor antagonists (H2RA) and proton pump inhibitors (PPIs) are effective in the treatment of GERD, but PPI therapy is clearly superior in the treatment of severe disease and in the healing of erosive esophagitis. A treatment schema for GERD based on presenting symptoms is outlined, promoting a stepwise approach to the appropriate use of antisecretory therapy.

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer.

Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

Patterns of proton pump inhibitor use in clinical practice.

BACKGROUND: Little is known about differences between gastroenterologists and primary care physicians in their patterns of prescribing proton pump inhibitors. SUBJECTS AND METHODS: A survey of practicing primary care physicians from the American Board of Medical Specialties and practicing gastroenterologists from the American Gastroenterological Association was conducted by facsimile. The survey instrument consisted of 13 questions about pharmacokinetics and administration of proton pump inhibitors. RESULTS: The overall response rate was 15% (491 of 3273), and 80% (395 of 491) of respondents were nontrainee gastroenterologists or primary care physicians. Approximately 90% (n = 355) of eligible respondents correctly identified proton pump inhibitors as inhibitors of H+,K+-adenosinetriphosphatase. Proton pump inhibitors were prescribed by 80% (n = 314) of each group for reflux esophagitis. They were prescribed by 67% (122 of 182) of gastroenterologists and 27% (58 of 213) of primary care physicians to prevent ulcers induced by nonsteroidal anti-inflammatory drugs (P <0.001). And they were prescribed by 40% (n = 73) of gastroenterologists and 16% (n = 34) of primary care physicians for uncomplicated heartburn (P <0.001). Proton pump inhibitors were prescribed before a meal by 95% (n = 173) of gastroenterologists and 33% (n = 70) of primary care physicians (P <0.001). Nearly 99% (n = 391) of respondents agreed that proton pump inhibitors were safe, but only 15% (n = 59) thought they should be available without prescription. CONCLUSION: Our survey suggests that the use of proton pump inhibitors differs between gastroenterologists and primary care physicians. Furthermore, although most physicians believe that proton pump inhibitors are safe, few believe that they should be available without a prescription.

Clinical potential of cyclo-oxygenase-2 inhibitors.

On the basis of their reduced potential to cause injury to the gastroduodenal mucosa, cyclo-oxygenase (COX)-2-selective inhibitors were developed and marketed as a safer alternative to traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This manuscript reviews the major steps leading to the introduction of COX-2-selective inhibitors into clinical practice, from the identification of the COX isoenzymes to their various roles in physiological and pathological processes. The available data show that COX-2 inhibitors have a favourable safety profile and are at least as effective as traditional NSAIDs for the treatment of pain and inflammatory conditions with a reduced incidence of gastrointestinal complications. Emerging evidence points to new and unanticipated effects from these agents. COX-2 inhibition appears to play an important role in the modulation of intestinal polyposis and colorectal carcinogenesis. Additionally, COX-2 expression may be associated with inflammatory responses leading to the occurrence of Alzheimer's disease and potentially, COX-2 inhibitors could be used to retard the progression of this condition. However, by decreasing prostacyclin production, COX-2 inhibitors may lead to increased prothrombotic activity and increase the risk of cardiovascular events. Until further large-scale prospective studies are performed, and the magnitude of these potential risks is quantified, COX-2 inhibitors should be used with caution in patients at risk for cardiovascular morbidity.

Design and development of the European American values scale for Asian Americans.

Existing instruments for measuring Asian American acculturation emphasize behavior acculturation to the exclusion of value acculturation. Most are based on the assumption that acquisition of European American behavior occurs simultaneously with the loss of Asian behavior. With the advent of the Asian Values Scale (AVS; B.S.K. Kim, D.R. Atkinson, & P.H. Yang, 1999), it is now possible to assess adherence to Asian cultural values. This article describes the development of a scale that can be used to measure Asian American adherence to European American values. The current scale, combined with the AVS, can be used to independently measure Asian American acculturation to European American values and enculturation in Asian values.

Cultural value similarities and differences among Asian American ethnic groups.

Using data on 570 Chinese, Filipino, Korean, and Japanese American college students from 3 previous studies (1 published [B. S. K. Kim, D. R. Atkinson, & P. H. Yang, 1999] and 2 unpublished [B. S. K. Kim, 1999; E. C. Wong, B. S. K. Kim, N. W. S. Zane, I. J. Kim, & J. S. Huang, 1999]), the authors subjected 22 items constituting 6 value dimensions of the Asian Values Scale (AVS; B. S. K. Kim et al., 1999) to the following structural equation modeling procedures: confirmatory factor analysis, factorial invariance analysis, and structured means analysis. The results of confirmatory factor analysis provided support for a hierarchical factor model when this model was compared with 2 competing models. The results of factorial invariance analysis indicated that the meanings of the factors within the hierarchical model were conceived similarly among the 4 Asian American ethnic groups. On the basis of these results, a structured means analysis was conducted, revealing similarities and differences between the ethnic groups' adherence to 6 cultural value dimensions. Implications regarding psychological services for these Asian Americans are discussed, and suggestions for future research are offered.

Glucose-dependent insulin release from genetically engineered K cells.

Genetic engineering of non-beta cells to release insulin upon feeding could be a therapeutic modality for patients with diabetes. A tumor-derived K-cell line was induced to produce human insulin by providing the cells with the human insulin gene linked to the 5'-regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells.

Nonsteroidal anti-inflammatory drugs.

NSAID-associated dyspeptic symptoms are common and can be managed empirically with an H2-receptor antagonist or a proton-pump inhibitor. Treatment of established gastroduodenal ulcers is accomplished best by withholding the offending drugs. Proton-pump inhibitors appear to heal ulcers at the same rate whether or not NSAID therapy is continued. After the ulcer is healed and if NSAID therapy must be continued, prophylaxis is accomplished best by the concomitant use of proton-pump inhibitors, misoprostol (at least 200 micrograms 3 times a day), or a NSAID that preferentially inhibits COX-2. The future development of newer, safer NSAID preparations, including highly selective COX-2 inhibitors and nitric oxide-releasing NSAIDs, should provide better treatment options for the increasing number of individuals requiring anti-inflammatory agents.

Regulation of glucose-dependent insulinotropic polypeptide release by protein in the rat.

Glucose-dependent insulinotropic polypeptide (GIP) release has been demonstrated predominantly after ingestion of carbohydrate and fat. These studies were conducted to determine the effects of protein on GIP expression in the rat. Whereas no significant changes in duodenal mucosal GIP mRNA levels were detected in response to peptone, the duodenal GIP concentration increased from 8.4+/-1.5 to 19.8+/-3.2 ng GIP/mg protein at 120 min (P<0.01). Plasma GIP levels also increased from 95+/-5.2 pg/ml to a peak of 289+/-56.1 pg/ml at 120 min (P<0.01). To determine whether the effects of protein on GIP were due to stimulation of acid secretion, rats were pretreated with 10 mg/kg omeprazole, after which mucosal and plasma GIP concentrations were partially attenuated. To further examine the effects of luminal acid, rats were administered intraduodenal 0.1 M HCl for 120 min, which significantly enhanced GIP expression. These studies indicate that nutrient protein provides a potent stimulus for GIP expression in the rat, an effect that occurs at the posttranslational level and may be mediated in part through the acid-stimulatory properties of protein. The effects of acid on GIP are consistent with a role for GIP as an enterogastrone in the rat.

Acute gastrointestinal bleeding in the intensive care unit. The gastroenterologist's perspective.

Although SRES-associated hemorrhage previously constituted a significant cause of bleeding in the ICU, improvements in ICU management and the institution of prophylactic measures in high-risk patients have significantly reduced SRES-associated hemorrhage since the 1980s. Antacids, H2-receptor antagonists, and sucralfate have been shown to be effective in preventing clinically significant bleeding resulting from SRES, particularly when the intragastric pH is maintained at greater than 4. A selective approach should be adopted in SRES prophylaxis: Patients on mechanical ventilation, with coagulopathy, or with two of the other known risk factors should receive prophylaxis. Although the drug of choice depends to some extent on local preferences, an H2-receptor antagonist by continuous intravenous infusion may represent the best option. No pharmacologic therapy is of proven value once hemorrhage begins, but the current interventional techniques are effective in controlling hemorrhage. Gastrointestinal bleeding from NOMV has become less common with improvements in the hemodynamic monitoring of critically ill patients, but this disease must always be considered when lower gastrointestinal bleeding occurs in the context of relative hypoperfusion. For SRES and NOMV, treatment of the underlying disease or diseases is the optimal route to prevention.