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Patel A, Spychalski P, Antoszewska M, Regula J, Kobiela J. Proton pump inhibitors and colorectal cancer: A systematic review. World J Gastroenterol 2021; 27:7716-7733. [PMID: 34908809 PMCID: PMC8641055 DOI: 10.3748/wjg.v27.i44.7716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 07/14/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk.
AIM To summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies.
METHODS This systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design.
RESULTS Data from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.
CONCLUSION An unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.
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Affiliation(s)
- Agastya Patel
- Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
| | - Piotr Spychalski
- Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
| | - Magdalena Antoszewska
- Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk 80-210, Poland
| | - Jaroslaw Regula
- Department of Gastroenterology, Hepatology and Oncology, Center of Postgraduate Medical Education, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw 01-813, Poland
| | - Jarek Kobiela
- Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
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Tatishchev SF, Vanbeek C, Wang HL. Helicobacter pylori infection and colorectal carcinoma: is there a causal association? J Gastrointest Oncol 2012. [PMID: 23205318 DOI: 10.3978/j.issn.2078-6891.2012.058] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Sergei F Tatishchev
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
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3
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Proton pump inhibitors: actions and reactions. Drug Discov Today 2009; 14:647-60. [PMID: 19443264 DOI: 10.1016/j.drudis.2009.03.014] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Revised: 01/15/2009] [Accepted: 03/31/2009] [Indexed: 12/14/2022]
Abstract
Proton pump inhibitors are the second most commonly prescribed drug class in the United States. The increased utilization of PPIs parallels the rising incidence of reflux disease. Owing to their clinical efficacy and relative lack of tachyphylaxis, PPIs have largely displaced H-2 receptor antagonists in the treatment of acid peptic disorders. The elevation of intragastric pH and subsequent alterations of gastric physiology induced by PPIs may yield undesired effects within the upper GI tract. The ubiquity of the various types of H(+), K(+)-ATPase could also contribute to non-gastric effects. PPIs may influence physiology in other ways, such as inducing transepithelial leak.
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Watson S. Section Review: Oncologic, Endocrine & Metabolic: Gastrin antagonists and gastrointestinal tumours. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.4.12.1253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Tolia V, Boyer K. Long-term proton pump inhibitor use in children: a retrospective review of safety. Dig Dis Sci 2008; 53:385-93. [PMID: 17676398 DOI: 10.1007/s10620-007-9880-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2007] [Accepted: 05/14/2007] [Indexed: 12/20/2022]
Abstract
The objective of this work was to assess the efficacy of continuous proton pump inhibitor (PPI) therapy in children and to evaluate changes in biochemical, endoscopic, and histologic parameters during such treatment. A retrospective review of children receiving PPI therapy continuously for 1 year or more with baseline and follow-up esophageal and gastric biopsies on treatment was conducted to assess type, frequency, and duration of PPI dosing, symptom relief, gastrin levels, histologic findings, and adverse events. A total of 113 children (59 male, median age 4.5 years) were identified. Of these, 31% (35/113) were neurologically impaired. The median treatment duration was 35.2 months. Elevated serum gastrin levels occurred in 73% of children with no statistically significant differences in gastrin level by PPI type, dose, and dosing frequency or treatment duration. Adverse events were reported by 12% of children: diarrhea (5%) and constipation (4%) were the most frequent. Long-term PPI therapy appears to be effective, safe and well tolerated in children despite some biochemical, endoscopic, and histologic changes.
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Affiliation(s)
- V Tolia
- Division of Gastroenterology, Children's Hospital of Michigan, Detroit, MI 48201, USA.
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Singh M, Dhindsa G, Friedland S, Triadafilopoulos G. Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic characteristics of colon adenomas. Aliment Pharmacol Ther 2007; 26:1051-61. [PMID: 17877512 DOI: 10.1111/j.1365-2036.2007.03450.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The clinical significance of the trophic effects of long-term proton pump inhibitors (PPI)-related hypergastrinemia on colon polyps remains unknown. AIM To study the frequency, growth, and histology of colon polyps in patients on chronic PPI therapy (cases), compared to those not receiving acid suppression (controls). METHODS Medical records of 2868 consecutive patients who underwent two or more colonoscopies, performed 3 or more months apart were reviewed. Cases (116) that used PPIs between the two colonoscopies were then compared to controls (194). RESULTS Demographics and risk factors for colon cancer were comparable between the two groups. At baseline the mean frequency and size of adenomatous polyps were similar in cases and controls (P > 0.05) and at follow-up, these were 0.89 and 1.18 (P > 0.05; 95% CI of -0.08 to 0.66) and 4.09 mm and 4.00 mm (P > 0.05; 95% CI -2.29 to 2.11), respectively with no significant change. However, control group had a higher mean frequency and size of hyperplastic polyps at baseline as well as at follow-up colonoscopy (P < 0.05). CONCLUSIONS The long-term use of PPI does not influence the frequency, growth, or histology of adenomatous polyps, but is associated with a reduction in both baseline and interval development of hyperplastic polyps.
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Affiliation(s)
- M Singh
- Gastroenterology Section, Veterans Affairs Health Care System, Palo Alto, CA, USA
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Hritz I, Herszenyi L, Molnar B, Tulassay Z, Pronai L. Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and epithelial growth factor receptor expression and has no effect on apoptosis and p53 expression. World J Gastroenterol 2005; 11:4721-6. [PMID: 16094717 PMCID: PMC4615418 DOI: 10.3748/wjg.v11.i30.4721] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of proton pump inhibitor (PPI) treatment on patients with reflux esophagitis and its in vivo effect on apoptosis, p53- and epidermal growth factor receptor (EGFR) expression.
METHODS: After informed consent was obtained, gastric biopsies of the antrum were taken from patients with reflux oesophagitis prior to and after 6 mo of 20 mg omeprazole (n = 14) or 40 mg esomeprazole (n = 12) therapy. Patients did not take any other medications known to affect the gastric mucosa. All patients were Helicobacter pylori negative as confirmed by rapid urease test and histology, respectively. Cell proliferation, apoptosis, EGFR, and p53 expression were measured by immunohistochemical techniques. At least 600 glandular epithelial cells were encountered and results were expressed as percentage of total cells counted. Was considered statistically significant.
RESULTS: Although there was a trend towards increase of cell proliferation and EGFR expression both in omeprazole and esomeprazole treated group, the difference was not statistically significant. Neither apoptosis nor p53 expression was affected.
CONCLUSION: Long-term PPI treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression.
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Affiliation(s)
- Istvan Hritz
- 2nd Dept Medicine, Semmelweis University, Budapest, Hungary.
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Ligumsky M, Lysy J, Siguencia G, Friedlander Y. Effect of long-term, continuous versus alternate-day omeprazole therapy on serum gastrin in patients treated for reflux esophagitis. J Clin Gastroenterol 2001; 33:32-5. [PMID: 11418787 DOI: 10.1097/00004836-200107000-00008] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Proton pump inhibitors have been proven to have a major role in the management of peptic diseases, especially the long-term control of reflux esophagitis. The potent inhibitory effect of omeprazole on gastric acid secretion is frequently associated with hypergastrinemia, and gastrin and its intermediates have been reported to promote gastrointestinal cellular functions and cell growth. Experimental data suggest that gastrin may affect the proliferation of colon cells and some other cancer cells. However, so far the direct role of gastrin in tumorigenesis is unclear. Although most clinical studies on long-term treatment with omeprazole or other proton pump inhibitors do not report serious adverse effects, the issue of prolonged hypergastrinemia and tissue growth is unsettled, and many clinicians are reluctant to recommend long-term use of omeprazole or of other proton pump inhibitors. STUDY We examined the effect of long-term omeprazole treatment on serum gastrin levels in patients with reflux esophagitis when given either 20 mg daily (group 1) or on alternate days (group 2). During the follow-up period, clinical remission was monitored and maintained in all patients in group 1 and in the majority of patients in group 2. RESULTS The mean serum gastrin level was significantly elevated in group 1 (mean +/- SE, 159 +/- 23.6 pg/mL; range, 45-620 pg/mL; n = 31) as compared with the alternate-day treatment group (group 2) (66 +/- 4.8 pg/mL; range, 37-115 pg/mL; n = 21) (p < 0.005). In controls, serum gastrin levels showed similar values to those found in group 2 (54 +/- 4.3 pg/mL; range, 27-94 pg/mL; n = 20). Fourteen patients (45%) in group 1 had serum gastric ranging from 140 to 620 pg/mL, and 8 (25%) had a 6-fold or greater increase in serum gastrin. The follow-up treatment period ranged between 3 and 60 months (mean +/- SE, 16.1 +/- 2.1 months) for group 1 and 3-36 months (9.7 +/- 1.4 months) for group 2. Upon multivariate adjustment for age and duration of treatment, a significantly lower mean serum gastrin level was observed in the alternate-day group as compared with the daily treated group. CONCLUSION Alternate-day, long-term treatment with omeprazole may be adequate to maintain remission in patients with reflux esophagitis. This regimen can assure serum gastrin levels within the normal range, thus reducing the potential risk of prolonged, sustained hypergastrinemia and profound hypochlorhydria.
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Affiliation(s)
- M Ligumsky
- Gastroenterology Unit, Division of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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9
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Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14:651-68. [PMID: 10848649 DOI: 10.1046/j.1365-2036.2000.00768.x] [Citation(s) in RCA: 182] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review examines the evidence for the development of adverse effects due to prolonged gastric acid suppression with proton pump inhibitors. Potential areas of concern regarding long-term proton pump inhibitor use have included: carcinoid formation; development of gastric adenocarcinoma (especially in patients with Helicobacter pylori infection); bacterial overgrowth; enteric infections; and malabsorption of fat, minerals, and vitamins. Prolonged proton pump inhibitor use may lead to enterochromaffin-like cell hyperplasia, but has not been demonstrated to increase the risk of carcinoid formation. Long-term proton pump inhibitor treatment has not been documented to hasten the development or the progression of atrophic gastritis to intestinal metaplasia and gastric cancer, although long-term studies are required to allow definitive conclusions. At present, we do not recommend that patients be tested routinely for H. pylori infection when using proton pump inhibitors for prolonged periods. Gastric bacterial overgrowth does increase with acid suppression, but important clinical sequelae, such a higher rate of gastric adenocarcinoma, have not been seen. The risk of enteric infection may increase with acid suppression, although this does not seem to be a common clinical problem with prolonged proton pump inhibitor use. The absorption of fats and minerals does not appear to be significantly impaired with chronic acid suppression. However, vitamin B12 concentration may be decreased when gastric acid is markedly suppressed for prolonged periods (e.g. Zolllinger-Ellison syndrome), and vitamin B12 levels should probably be assessed in patients taking high-dose proton pump inhibitors for many years. Thus, current evidence suggests that prolonged gastric acid suppression with proton pump inhibitors rarely, if ever, produces adverse events. Nevertheless, continued follow-up of patients taking proton pump inhibitors for extended periods will provide greater experience regarding the potential gastrointestinal adverse effects of long-term acid suppression.
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Affiliation(s)
- L Laine
- University of Southern California School of Medicine, Los Angeles, California 90033, USA.
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10
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Robinson M. Review article: current perspectives on hypergastrinaemia and enterochromaffin-like-cell hyperplasia. Aliment Pharmacol Ther 1999; 13 Suppl 5:5-10. [PMID: 10555603 DOI: 10.1046/j.1365-2036.1999.00033.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Rabeprazole, a new benzimidazole proton pump inhibitor (PPI), is among a class of agents known to be very potent inhibitors of gastric acid secretion. PPIs inhibit hydrogen-potassium adenosine triphosphatase activity on the luminal surface of the parietal cell, effectively blocking the final common pathway for gastric acid secretion. Raising gastric pH stimulates the production of gastrin by G cells in the antrum of the stomach, which can lead to enterochromaffin-like (ECL)-cell hyperplasia. In the past, these changes have been viewed with concern, particularly in the light of studies in rats indicating that hypergastrinaemia and ECL-cell hyperplasia induce gastric carcinoid tumour formation. All available clinical data indicate that long-term PPI use does not lead to carcinoid tumour formation in humans. In fact, both serum gastrin elevation and ECL-cell hyperplasia are now generally viewed as normal physiological responses to gastric acid suppression. Serum gastrin concentrations, in particular, correlate well with gastric acid suppression, which has led to the use of gastrin response by some investigators as a surrogate marker of antisecretory effectiveness. Long-term tolerability data indicate that PPIs have a favourable side-effect profile. Data obtained from patients receiving acute or long-term maintenance rabeprazole therapy support this conclusion. Furthermore, neither animal nor human data obtained with rabeprazole suggest a significant risk for neoplastic changes secondary to hypergastrinaemia.
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Affiliation(s)
- M Robinson
- University of Oklahoma College of Medicine, Oklahoma Foundation for Digestive Research, Oklahoma City, USA.
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11
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Abstract
In addition to its fundamental role in stimulating gastric acid secretion, the peptide hormone gastrin induces growth-promoting effects on diversity of target cells. Various mechanisms, including endocrine, paracrine, and autocrine, have been proposed for gastrin's growth-promoting actions. The mitogenic effects of gastrin are mediated by specific cell surface receptors activated after gastrin binding. The functionally defined receptors for gastrin include cholecystokinin A (CCKA) receptor, which is discriminating for sulfated CCK8; cholecystokinin B (CCKB)/gastrin receptor, which binds gastrin17 sulfated, and nonsulfated CCK8 with nearly equal affinities; cholecystokinin C (CCKC), which is a low-affinity gastrin binding protein; and novel, high-affinity receptors selective for amidated gastrin, processing intermediates of gastrin, or both. The signaling pathways mediating gastrin's stimulation of the CCKB/gastrin receptor have been progressively outlined, and the pathways mediating other receptors have been slowly emerging. Engagement of the gastrin receptor initiates various biochemical and molecular events, including recruitment and activation of tyrosine kinases, activation of the phospholipase C signaling pathway leading to phosphoinositide breakdown, intracellular calcium mobilization and protein kinase C stimulation, activation of the mitogen-activated protein kinase pathway, and induction of early response genes. Current emphasis is on understanding the functional significance of processing intermediate forms of gastrin, and the receptor subtypes and pathways that promote the trophic/mitogenic effects of the different molecular forms of gastrin.
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Affiliation(s)
- R R Yassin
- Department of Medicine, MCP Hahnemann University, Philadelphia, PA 19102-1192, USA
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12
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Orbuch M, Venzon DJ, Lubensky IA, Weber HC, Gibril F, Jensen RT. Prolonged hypergastrinemia does not increase the frequency of colonic neoplasia in patients with Zollinger-Ellison syndrome. Dig Dis Sci 1996; 41:604-13. [PMID: 8617144 DOI: 10.1007/bf02282349] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Whereas considerable experimental evidence suggests chronic hypergastrinemia can increase the occurrence of colonic neoplasia, the risks in man remain unclear. Zollinger-Ellison syndrome (ZES) is associated with marked plasma elevation of all forms of gastrin and, because of its prolonged course, has been shown to be an excellent model disease to study the effects of chronic hypergastrinemia in man. To determine whether profound chronic hypergastrinemia affects the occurrence of colonic dysplasia and neoplasia, 97 consecutive patients with ZES were studied. All patients underwent colonoscopic examination to the cecum, and the location, size, and type of polyps/tumors were determined. The patients had a mean fasting gastrin level 31 times above normal and a mean disease duration of 10 years; 17/97 (18%) had adenomatous polyps, 67/97 (69%) no adenomatous polyps, and 2/97 (2%) had colonoscopy and/or autopsy studies fo asymptomatic controls. Stratification by age or gender, presence of MEN-I, tumor extent, and duration of degree of hypergastrinemia did not increase prevalence. This study shows that despite prolonged, profound hypergastrinemia, no increased rate of colonic neoplasia (polyps or cancer) was noted. These data suggest that the development of hypergastrinemia secondary to continuous use of H+,K+-ATPase inhibitors for as long as 10 years is unlikely to cause an increased risk of developing colonic neoplasia in man.
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Affiliation(s)
- M Orbuch
- Digestive Diseases Branch, National Institue of Diabetes and Digestive and Kidney Diseases, National Institues of Health, Bethesda, Maryland 20892, USA
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Chu M, Nielsen FC, Franzén L, Rehfeld JF, Holst JJ, Borch K. Effect of endogenous hypergastrinemia on gastrin receptor expressing human colon carcinoma transplanted to athymic rats. Gastroenterology 1995; 109:1415-20. [PMID: 7557120 DOI: 10.1016/0016-5085(95)90625-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS The effect of endogenous hypergastrinemia on growth of human colon carcinoma is not known. Our aim was to study the growth of human colon carcinoma in an animal model with endogenous hypergastrinemia. METHODS Human colon carcinoma was transplanted to the colon of 40 athymic rats. Of these, 25 underwent gastric fundectomy to accomplish endogenous hypergastrinemia, and 15 were sham operated to serve as controls. The duration of the study was 8 weeks. During the last week, 12 fundectomized animals received a gastrin (cholecystokinin B) receptor antagonist. Metaphase arrest index, local invasion, and distant spread of the tumor were investigated. Expression of gastrin and cholecystokinin B receptor messenger RNA was examined by reverse-transcription polymerase chain reaction. RESULTS Tumor spread by direct extension outside the colon was observed in all animals, and liver metastases were observed in 10 of the 25 fundectomized animals. Sham-operated animals showed none of these features. The metaphase arrest index of the tumor did not differ between fundectomized animals given the cholecystokinin B receptor antagonist and sham-operated animals, whereas it was significantly increased in fundectomized animals not given the antagonist. The tumor expressed both gastrin and cholecystokinin B receptor messenger RNA. CONCLUSIONS The results indicate that endogenous hypergastrinemia may promote proliferation and spread of human colon carcinoma expressing cholecystokinin B receptor.
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Affiliation(s)
- M Chu
- Department of Surgery, University Hospital of Linköping, Sweden
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Pinson DM, Havu N, Sztern MI, Mattsson H, Looney GA, Kimler BF, Hurwitz A. Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats. Gastroenterology 1995; 108:1068-74. [PMID: 7698573 DOI: 10.1016/0016-5085(95)90204-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND/AIMS Published studies suggest that hypergastrinemia stimulates growth of normal or malignant colon tissue. Other studies dispute these findings. This study was designed to test the hypothesis that hypergastrinemia enhances progression or invasiveness of colon cancer. METHODS Colonic carcinomas were induced in male Sprague-Dawley rats by six weekly intraperitoneal injections of methylazoxymethanol. Four weeks after the last injection of carcinogen, the animals were randomized into four treatment groups, including vehicle control, low- and high-dose omeprazole, and ranitidine. After 10 weeks of treatment, the animals were bled, stomach weights were recorded, and colon tumors were mapped, enumerated, measured, and scored histopathologically by Dukes' classification. Crypt and mucosal heights were determined in colonic mucosa unaffected by tumor. RESULTS Drug administration induced a sustained hypergastrinemia that did not enhance tumor burden or invasiveness or crypt height/mucosal height ratios. Ranitidine-treated rats consumed less food, weighed less, and developed fewer tumors. This group also had lower crypt and mucosal heights than rats in the vehicle- or omeprazole-treated rats. CONCLUSIONS The results suggest that endogenous hypergastrinemia induced by these acid-suppressing drugs has no stimulatory effect on colon mucosal growth or progression or biological behavior of experimental rat colon cancer.
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Affiliation(s)
- D M Pinson
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City
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16
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Abstract
Gastrin and cholecystokinin (CCK) act as growth factors for the gastric mucosa and the pancreas, respectively. CCK is also responsible, via the CCK-A receptor, for the pancreatic hyperplasia observed following the feeding of protease inhibitors or pancreaticobiliary diversion. Hypergastrinaemia does not increase the incidence of spontaneous gastrointestinal carcinoma, but does stimulate the proliferation of gastric enterochromaffin-like cells via the gastrin/CCK-B receptor, with a consequent increase in the incidence of gastric carcinoids. Whether gastrin influences mutagen-induced gastrointestinal carcinogenesis is still controversial, but CCK clearly enhances the induction by carcinogens of acinar tumours in the pancreas. While gastrin increases xenograft growth of 50% of gastrointestinal tumours tested, effects on the proliferation of gastrointestinal tumour cell lines in vitro have been more difficult to demonstrate, perhaps because many cell lines are already maximally stimulated by autocrine gastrin. Gastrin mRNA and progastrin, but not mature amidated gastrin, have been detected in all gastrointestinal cell lines tested. Although cell proliferation is inhibited by gastrin/CCK receptor antagonists, the spectrum of antagonist affinities is not consistent with binding to either CCK-A or gastrin/CCK-B receptors. Definition of the molecular structure of the receptor involved in the autocrine loop may lead to novel therapies for gastrointestinal cancer.
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Affiliation(s)
- G S Baldwin
- Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Parkville, Victoria, Australia
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17
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Abstract
PURPOSE Confirmation of an association between elevated serum gastrin concentrations and presence of colorectal tumors would have important implications with regard to screening procedures and therapeutic strategies. METHODS We compared fasting serum gastrin concentrations of patients with colorectal cancer (n = 91; mean age, 66 (range, 35-87) years), colorectal polyps (n = 89; mean age, 61 (range, 38-86) years), or a normal colonoscopy (n = 101; mean age, 62 (range, 34-82) years) in the period between 1983 and 1992. RESULTS Median serum gastrin concentrations were, respectively, 20, 20, and 21 pmol/liter (not significant). We were unable to find a relation with histology of the polyp, presence or severity of dysplasia, and extent of cancer. CONCLUSIONS This large study fails to show any difference in serum gastrin concentrations among the three studied groups.
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Affiliation(s)
- J F Rehfeld
- Department of Clinical Biochemistry, University of Copenhagen, Rigshospitalet, Denmark
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Penman ID, el-Omar E, McGregor JR, Hillan KJ, O'Dwyer PJ, McColl KE. Omeprazole inhibits colorectal carcinogenesis induced by azoxymethane in rats. Gut 1993; 34:1559-65. [PMID: 8244144 PMCID: PMC1374422 DOI: 10.1136/gut.34.11.1559] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Numerous clinical and experimental studies suggest that gastrin plays an important part in the development of colorectal cancer in humans. This study was done to assess the influence of omeprazole induced hypergastrinaemia on the development of colorectal tumours in an experimental animal model. Forty female Sprague-Dawley rats received either omeprazole (40 mumol/kg) or vehicle (0.25% methylcellulose) by once daily oral gavage throughout the experiment. All animals received 12 consecutive weekly subcutaneous injections of azoxymethane (10 mg/kg/week) beginning at week 6. Serum gastrin concentrations were measured during weeks 1 and 5 and at death (week 27). Chronic omeprazole treatment resulted in appreciable hypergastrinaemia during the study, mean gastrin concentrations in omeprazole treated rats being raised by up to nine to 10 fold, compared with vehicle treated control rats (p < 0.001). Despite this, tumour incidence in the omeprazole group was significantly lower at 63%, compared with 95% in the vehicle only group (p < 0.02). The median number of tumours in the omeprazole group (1) compared with the vehicle group (3) was also significantly lower (p = 0.02). Average tumour size, site distribution, and the comparative frequencies of adenomas and adenocarcinomas were similar in the two groups. This study shows that omeprazole protects against colorectal carcinogenesis in this model despite causing appreciable hypergastrinaemia. The mechanism by which this occurs is unclear and merits further investigation. Because of the compounding protective effects of omeprazole, this model is not a suitable one for studying the longterm trophic effects of gastrin on the colon.
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Affiliation(s)
- I D Penman
- University Department of Medicine and Therapeutics, Western Infirmary, Glasgow
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Sobhani I, Lehy T, Laurent-Puig P, Cadiot G, Ruszniewski P, Mignon M. Chronic endogenous hypergastrinemia in humans: evidence for a mitogenic effect on the colonic mucosa. Gastroenterology 1993; 105:22-30. [PMID: 8514038 DOI: 10.1016/0016-5085(93)90006-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Information concerning the influence that gastrin may exert on the colon is fragmentary and somewhat controversial. This study analyzed the effect of chronic endogenous hypergastrinemia on cell proliferation and tumor occurrence in the human colonic mucosa. METHODS Twenty-three consecutive hypergastrinemic patients presenting with the Zollinger-Ellison syndrome and 18 normogastrinemic subjects were studied. All had fasting serum gastrin determination, colonoscopy, and cell kinetic measurement in two colonic sites using in vitro 5'-bromodeoxyuridine incorporation. RESULTS Macroscopic tumors, one endocrine and five adenomas, were found in 5 of 23 hypergastrinemic patients, without apparent relationship with the level of gastrin. The labeling indices were significantly higher in hypergastrinemic than in normogastrinemic individuals in the right and left colon, (P < 0.002 to P < 0.001) without resulting in colonic cell hyperplasia. There was no correlation between labeling indices and serum gastrin concentrations or duration of hypergastrinemia. The DNA labeling distribution along the crypt was normal in the two groups, without expansion of the proliferative zone towards the surface. CONCLUSIONS These results showed for the first time that long-lasting endogenous hypergastrinemia is accompanied by increased in vivo cell proliferation in the human colonic mucosa. However, the prevalence of adenomas (17.4%) in patients, all more than 50 years old, may not be different from that in the general population.
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Affiliation(s)
- I Sobhani
- INSERM U 10, Hôpital Bichat-Claude Bernard, Paris, France
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Lüttichau HR, Van Solinge WW, Nielsen FC, Rehfeld JF. Developmental expression of the gastrin and cholecystokinin genes in rat colon. Gastroenterology 1993; 104:1092-8. [PMID: 8462797 DOI: 10.1016/0016-5085(93)90278-k] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND To elucidate the hypothesis that gastrin and cholecystokinin (CCK) are local growth factors for colorectal mucosa, we have examined the peptide gene expression in rat colon during development. METHODS Northern analysis, reverse transcription PCR, and sequence-specific radioimmunoassays were the essential methods. RESULTS High concentrations of gastrin and CCK messenger RNA were found in the fetal colon. At birth, gastrin and CCK mRNA's were both undetectable but increased subsequently towards adult life. The fetal colon contained 5.5 and 4.2 pmol/g tissue gastrin and CCK, respectively. After birth, carboxyamidated gastrin disappeared from the colon, whereas the concentration of CCK remained at 1 pmol/g. Glycine-extended gastrin and CCK were also present in the fetal colon, but towards adult life they decreased below 0.2 pmol/g. In contrast, progastrin and proCCK were detectable at all ages. CONCLUSIONS Rat colon expresses the gastrin and CCK genes throughout life. The posttranslational maturation of progastrin, however, ceases shortly after birth, indicating that gastrin may play a role in the developing colon. Whether CCK influences the development remains to be shown.
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Affiliation(s)
- H R Lüttichau
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Denmark
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Abstract
This article takes the reader from colorectal lumen to the intracellular environment in an effort to explain the processes of tumorigenesis in colorectal cancer. The molecular changes seen in colorectal cancer development also are discussed, along with the potential for genetic manipulation and diagnostic molecular techniques. An era of major advances in understanding the pathogenesis of colorectal cancer has begun.
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Affiliation(s)
- J W Milsom
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Ohio
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