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Biomedical subjects

P E O'Brien

Publications and source records attributed to P E O'Brien.

At least 37 records · Page 2Linked to original sources

Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation.

Nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorectal cancer by 40-50%. Previous studies suggest that effective inhibition of colorectal cancer by NSAIDs may be dependent on the presence or absence of a K-ras mutation. This study was aimed at determining the relationship between inhibition of colorectal cancer by sulindac and sulindac sulfone and the presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihydrochloride rat model. Sulindac (20 mg x kg(-1) x day(-1)), sulindac sulfone (40 mg x kg(-1) x day(-1)), or vehicle was administered orally to male Sprague-Dawley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor number and volume were measured before treatment by laparotomy and colonoscopy and again after treatment. Sulindac and sulindac sulfone treatment significantly reduced the number and volume of colorectal tumors compared with control rats. For K-ras (codon 12) mutation detection, frozen tumor tissue was collected at the endpoint. We found K-ras codon 12 mutations in 11 of 21 (52%) control tumors. The proportion of tumors with K-ras mutations in the sulindac-treated group [5 of 8 (62%); odds ratio = 1.51 (95% confidence interval = 0.29, 8.33)] and the proportion of sulindac sulfone-treated tumors [9 of 14 (64%); odds ratio = 1.63 (95% confidence interval = 0.41, 6.66)] were not significantly different from controls. Tumor inhibition did not correlate with K-ras (codon 12) mutation status, which suggests that the mechanism of inhibition of rat colorectal cancer by sulindac and sulindac sulfone is independent of K-ras mutation.

1,2-Dimethylhydrazine↗

Cyclooxygenase-1 and an alternatively spliced mRNA in the rat stomach: effects of aging and ulcers.

Prostaglandins play a critical role in gastric mucosal cytoprotection and decrease progressively with age. Cyclooxygenase (COX), the rate-limiting enzyme for prostaglandin synthesis, exists in two isoforms, COX-1 and COX-2. The rat COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) that may, at best, code for a truncated COX-1 protein. With the use of competitive PCR, we determined whether COX gene expression was altered in the stomach with increasing age and after gastric ulcer induction. COX-1 mRNA was significantly reduced in the aged, and COX-1SV mRNA was significantly higher in the adults compared with the young and aged stomach. Levels of COX-1 and COX-2 were similarly expressed in the normal stomach. In acute gastric ulcers, only COX-2 mRNA levels were significantly elevated. When ulcers were undergoing healing and repair, COX-1 and COX-2 mRNA levels were significantly elevated. Age-related changes in COX-1 and COX-1SV but not COX-2 mRNA may alter gastric mucosal cytoprotection. Furthermore, COX-1 and COX-2 may both contribute to the healing of a gastric ulcer.

Aging↗

Prospective study of a laparoscopically placed, adjustable gastric band in the treatment of morbid obesity.

BACKGROUND: Surgical control of morbid obesity should benefit from a minimally invasive approach and the ability to adjust the degree of gastric restriction. METHODS: The Lap-Band adjustable gastric banding system was evaluated prospectively in a consecutive series of 302 patients, and data on perioperative outcome and weight loss pattern at up to 4 years of follow-up are presented. Some 302 patients (89 per cent women; mean age 39 years, mean weight 124 kg) were entered into the study. Laparoscopic placement was used in 277 patients. Previous gastric stapling surgery was the principal reason for an elective open approach. RESULTS: The incidence of significant early complications was 4 per cent and included two perforations of the stomach after open placement. The mean length of stay after laparoscopic placement was 3.9 days and only one complication (infected reservoir site) occurred in these patients. The principal late complication of prolapse of the stomach through the band occurred in 27 patients (9 per cent). Significant modification of technique and patient care has enabled reduction of this complication in the latter part of the series. Mean(s.d.) excess weight loss was 51.0(17) per cent at 12 months (n = 120), 58.3(20) per cent at 24 months (n = 43), 61.6(2) per cent at 36 months (n = 25) and 682(21) per cent at 48 months (n = 12). CONCLUSION: The Lap-Band is an effective method for achieving good weight loss in the morbidly obese at up to 4 years of follow-up. Laparoscopic placement has been associated with a short length of stay and a low frequency of complications. The ability to adjust the setting of the device to achieve different degrees of gastric restriction has enabled progressive weight loss throughout the period of study.

Adolescent↗

Prediction of outcome in intensive care unit trauma patients: a multicenter study of Acute Physiology and Chronic Health Evaluation (APACHE), Trauma and Injury Severity Score (TRISS), and a 24-hour intensive care unit (ICU) point system.

OBJECTIVE: To conduct a multicenter study to validate the accuracy of the Acute Physiology and Chronic Health Evaluation (APACHE) II system, APACHE III system, Trauma and Injury Severity Score (TRISS) methodology, and a 24-hour intensive care unit (ICU) point system for prediction of mortality in ICU trauma patient admissions. METHODS: The study population consisted of retrospectively identified, consecutive ICU trauma admissions (n = 2,414) from six Level I trauma centers. Probabilities of death were calculated by using logistic regression analysis. The predictive power of each system was evaluated by using decision matrix analysis to compare observed and predicted outcomes with a decision criterion of 0.50 for risk of hospital death. The Youden Index (YI) was used to compare the proportion of patients correctly classified by each system. Measures of model calibration were based on goodness-of-fit testing (Hosmer-Lemeshow statistic less than 15.5) and model discrimination were based on the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, APACHE II (sensitivity, 38%; specificity, 99%; YI, 37%; H-L statistic, 92.6; AUC, 0.87) and TRISS (sensitivity, 52%; specificity, 94%; YI, 46%; H-L statistic, 228.1; AUC, 0.82) were poor predictors of aggregate mortality, because they did not meet the acceptable thresholds for both model calibration and discrimination. APACHE III (sensitivity, 60%; specificity, 98%; YI, 58%; H-L statistic, 7.0; AUC, 0.89) was comparable to the 24-hour ICU point system (sensitivity, 51%; specificity, 98%; YI, 50%; H-L statistic, 14.7; AUC, 0.89) with both systems showing strong agreement between the observed and predicted outcomes based on acceptable thresholds for both model calibration and discrimination. The APACHE III system significantly improved upon APACHE II for estimating risk of death in ICU trauma patients (p < 0.001). Compared with the overall performance, for the subset of patients with nonoperative head trauma, the percentage correctly classified was decreased to 46% for APACHE II; increased to 71% for APACHE III (p < 0.001 vs. APACHE II); increased to 59% for TRISS; and increased to 62% for 24-hour ICU points. For operative head trauma, the percentage correctly classified was increased to 60% for APACHE II; increased to 61% for APACHE III; decreased to 43% for TRISS (p < 0.004 vs. APACHE III); and increased to 54% for 24-hour ICU points. For patients without head injuries, all of the systems were unreliable and considerably underestimated the risk of death. The percentage of nonoperative and operative patients without head trauma who were correctly classified was decreased, respectively, to 26% and 30% for APACHE II; 33% and 29% for APACHE III; 33% and 19% for TRISS; 20% and 23% for 24-hour ICU points. CONCLUSION: For the overall estimation of aggregate ICU mortality, the APACHE III system was the most reliable; however, performance was most accurate for subsets of patients with head trauma. The 24-hour ICU point system also demonstrated acceptable overall performance with improved performance for patients with head trauma. Overall, APACHE II and TRISS did not meet acceptable thresholds of performance. When estimating ICU mortality for subsets of patients without head trauma, none of these systems had an acceptable level of performance. Further multicenter studies aimed at developing better outcome prediction models for patients without head injuries are warranted, which would allow trauma care providers to set uniform standards for judging institutional performance.

APACHE↗

Gastroesophageal reflux in obesity: the effect of lap-band placement.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition which is often aggravated by morbid obesity. Lap-Band surgery provides effective weight loss in the morbidly obese. There have been several reports that gastric banding causes or aggravates reflux. The aim of this study was to evaluate the effect of Lap-Band placement on GERD. METHODS: All patients with a significant history of GERD who had a Lap-Band inserted over a 2-year period were evaluated postoperatively to assess any change in impact on reflux. Resolution required absence of reflux symptoms and no anti-reflux drug therapy. RESULTS: There were 48 (16%) of 274 consecutive patients with a significant history of reflux esophagitis requiring regular therapy preoperatively. The median age was 39 (range 23-58) and M:F ratio was 5:43. We confirm a high prevalence of GERD in patients with morbid obesity: 17% with symptoms requiring regular therapy (Community Norm 7%). Total resolution of all reflux symptoms occurred in 36 (76%) patients, improvement in 7 (14%), no change in 3 (6%), and aggravation of symptoms in 2 (4%). Patients with severe and moderate symptoms had similar improvement. Resolution or improvement was reported soon after surgery. CONCLUSION: Rapid and major improvement in symptoms of GERD occurs after Lap-Band placement. The placement of the band probably acts directly to reduce reflux. This result contrasts with reports which have found gastric banding causes or aggravates GERD.

Adolescent↗

Tamoxifen inhibits colorectal cancer metastases in the liver: a study in a murine model.

Liver metastases account for over 70% of deaths resulting from colorectal carcinoma, with survival rates varying between 6-18 months. At present, surgical resection offers the only hope for a cure, while chemotherapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is primarily known for treating oestrogen receptor (ER)-positive breast cancer. Some studies suggest that tamoxifen may have beneficial effects in malignancies other than breast cancer. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanisms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this model, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results in secondary tumour deposits in the liver in virtually all animals. Tamoxifen was administered at a dose of 1 mg/kg suspended in 1.0% methyl cellulose. The control group received an equal volume of the vehicle. The reagents were administered s.c. on the day of metastases induction and were continued daily over a 4 week period. The effect of tamoxifen on tumour growth was assessed by stereology and bromodeoxyuridine immunohistochemistry at selected time points. Data were assessed by a multiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 +/- 41 mm3 at day 10 to 517 +/- 380 mm3, 1394 +/- 598 mm3 and 2082 +/- 675 mm3 by days 16, 22 and 28, respectively. Daily administration of tamoxifen exerted an inhibitory effect on tumour growth during the first 3 weeks, recording a volume of 421 +/- 299 mm3 by day 22 compared with the control group at that time point (P = 0.00004). The inhibitory effect diminished by the fourth week recording a tumour volume of 1344 +/- 674 mm3 by day 28. Inhibition of tumour growth at day 22 coincides with a reduction of cells in the S phase of the cell cycle. The percentage of brdU-positive nuclear profiles in metastases of tamoxifen-treated mice at 3 weeks was 35.87 +/- 5.60% compared with 48.01 +/- 3.96% in the control group (P = 0.001). These data suggest that tamoxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.

Animals↗

Tiaprofenic acid inhibits mucosal prostaglandin E2 synthesis without delaying experimental gastric ulcer healing.

Increasing evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) differ in gastrotoxicity. This study aimed to compare the effects of a short-acting NSAID, tiaprofenic acid, with indomethacin on experimental gastric ulcer healing in a rat model. Similar anti-inflammatory and prostaglandin-inhibitory doses of indomethacin (1 mg/kg) and tiaprofenic acid (2 mg/kg) were administered to rats with acetic acid-induced ulcers. After 2 weeks treatment, rats were killed and ulcer size determined. In addition, histological sections of ulcers were assessed for ulcer contraction and mucosal regeneration. The degree of inhibition of prostaglandin E2 (PGE2) synthesis was 72% at 2 h after tiaprofenic acid and 64% at 2 h after indomethacin administration, respectively. Rats treated with indomethacin for 2 weeks had significantly larger ulcers, both macroscopically and microscopically, than controls. Rats treated with tiaprofenic acid for 2 weeks had ulcers of a similar size to those of controls. Indomethacin-treated ulcers showed a failure in mucosal regeneration. Tiaprofenic acid-treated ulcers had significantly more regeneration than indomethacin-treated ulcers. We conclude that tiaprofenic acid inhibits mucosal prostaglandin levels but does not inhibit experimental gastric ulcer healing. These findings suggest that inhibition of PGE2 synthesis is not the only factor in generating gastrotoxicity and that a shift to low gastrotoxic NSAID may be clinically worthwhile.

Animals↗

Sulindac inhibits colorectal tumour growth, but not prostaglandin synthesis in the rat.

We have determined the dose-response relationship between sulindac administration and inhibition of tumour growth in the rat. The effect of tumour-inhibiting doses of sulindac on the production of prostaglandin E in tumours and macroscopically normal colon was then examined. Growth of pre-existing tumours was significantly reduced following administration of sulindac at 0.1 (P=0.004), 1 (P=0.01), 3 (P<0.001) and 10 mg/kg b.d. (P=0.002) for 4 weeks. There was no significant difference in prostaglandin E synthesis between tumours from control rats and those treated with sulindac at either 3 or 10 mg/kg b.d. (P=0.09 and 0.4, respectively). Prostaglandin E synthesis was reduced by 33 and 32% in macroscopically normal tissue from these treatment groups. These data show that sulindac inhibits tumour growth at low doses and do not support a role for the inhibition of prostaglandin synthesis, by sulindac, in the inhibition of tumour growth.

Animals↗

Expression of adhesion molecules and leukocyte recruitment into gastric mucosa following ischemia-reperfusion.

Leukocyte infiltration is an important step in postischemic tissue damage. This study aimed to determine the expression of adhesion molecules and their relationship with leukocyte infiltration in the postischemic gastric mucosa. Gastric tissue was obtained from rats subjected to 30 min gastric ischemia followed by reperfusion. Sections were stained with specific antibodies against (1) L-selectin and (2) LFA-1 on leukocytes, (3) ICAM-1 on endothelial cells, (4) PMNs, and (5) monocytes. Stained cells or blood vessels in mucosal tissue were counted using image analysis. Results showed that from 5 min of reperfusion, numbers of L-selectin-positive cells decreased, whereas LFA-1-positive cells and PMNs increased compared with controls. ICAM-1 expression did not increase until 60 min of reperfusion. Monocyte numbers were unaffected by reperfusion. We conclude that gastric ischemia-reperfusion results in a rapid influx of LFA-1-positive cells, the majority of which are PMN. L-Selectin is shed from these cells allowing them to adhere to the microvasculature via constitutively expressed ICAM-1.

Animals↗

Changes in sulfated macromolecules produced in vivo during normal and indomethacin-delayed ulcer healing in rats.

The aim of this study was to examine the synthesis of sulfated glycosaminoglycans during normal healing of experimental acetic acid-induced gastric ulcer in rats and to investigate the effect of indomethacin, a drug known to delay ulcer healing, on this synthesis using an in vivo labelling system. Analysis revealed the presence of two major sulfated species in control tissue; a population of sulfated mucins and glycosaminoglycans, predominantly galactosaminoglycans. The incorporation of [35S]sulfate label into glycosaminoglycans synthesized in the granulation tissue of healing ulcers increased significantly (P < 0.05) as compared to day 0 and control levels at day 14. Treatment of animals with indomethacin (1 mg/kg daily) resulted in a further significant (P < 0.01) rise in sulfated glycosaminoglycan synthesis in indomethacin-treated ulcer tissue compared to that found in healing ulcers at day 14. The increased glycosaminoglycan synthesis was due to increased levels of chondroitin sulfate and dermatan sulfate. Glycosaminoglycan synthesis is elevated at the ulcer site during healing of experimental gastric ulcers; however, indomethacin treatment, which delays ulcer healing, significantly increases the synthesis of glycosaminoglycans above that seen in healing ulcers. Changes in the sulfated glycosaminoglycan content of the ulcer may play a role in the healing process and may give further insight into the mechanisms by which indomethacin delays ulcer healing.

Acetic Acid↗

Microvascular architecture of hepatic metastases in a mouse model.

Development of effective treatment for hepatic metastases can be initiated by a better understanding of tumour vasculature and blood supply. This study was designed to characterise the microvascular architecture of hepatic metastases and observe the source of contributory blood supply from the host. Metastases were induced in mice by an intrasplenic injection of colon carcinoma cells (10(6) cells/ml.) Vascularization of tumours was studied over a three week period by scanning electron microscopy of microvascular corrosion casts. Metastatic liver involvement was observed initially within a week post induction, as areas approximately 100 microns in diameter not perfused by the casting resin. On histology these spaces corresponded to tumour cell aggregates. The following weeks highlighted the angiogenesis phase of these tumours as they received a vascular supply from adjacent hepatic sinusoids. Direct sinusoidal supply of metastases was maintained throughout tumour growth. At the tumour periphery most sinusoids were compressed to form a sheath demarcating the tumour from the hepatic vasculature. No direct supply from the hepatic artery or the portal vein was observed. Dilated vessels termed vascular lakes dominated the complex microvascular architecture of the tumours, most tapering as they traversed towards the periphery. Four vascular branching patterns could be identified as true loops, bifurcations and trifurcations, spirals and capillary networks. The most significant observation in this study was the direct sinusoidal supply of metastases, together with the vascular lakes and the peripheral sinusoidal sheaths of the tumour microculature.

Animals↗

The microvascular structure of the normal colon in rats and humans.

The colonic microcirculation may be expected to have a central role in the absorptive, secretory, and protective functions of the colon. To characterize the microvascular structure of the colon in rats and humans, microvascular casts were prepared and examined by scanning electron microscopy. Quantitative measures of the microvasculature were obtained from histological sections. The overall organization of microvessels was found to be similar in the rat and human colon. Capillaries in the colonic mucosa formed a honeycomb-like network around each of the mucosal glands. This capillary plexus was supplied by arterioles which divide into their capillary branches at the level of the submucosa. Mucosal capillaries drain into venules at the luminal surface of the mucosa. Venules then pass to submucosal veins without receiving further capillary branches. Examination of vascular casts also showed that in both the rat and the human colon, there was an increased density of subluminal capillaries in the cecum and proximal colon compared to that of the rest of the colon. This was supported by quantitative measures which indicated a significantly greater microvascular surface area in the rat cecum (24.1 mm2/mm3) compared to that of the midcolon (19.8 mm2/mm3) (P = 0.04) and the distal colon (19.1 mm2/mm3) (P = 0.03). Similarly in the human colon there was a significantly greater total microvascular volume in the proximal colon (13.4%) compared to that of the distal colon (7.7%) (P < 0.0005) and there was a significantly greater total microvascular surface area in the proximal colon (22.4 mm2/mm3) compared to that of the distal colon (17.5 mm2/mm3)(P=0.032). This study details quantitative vascular data for the colon in rats and humans which has not previously been documented, despite its important role in the absorptive function of the colon and in many disease processes affecting the colon. These data provide the normal values with which pathological conditions of the colon which affect the vasculature can be compared.

Animals↗

Influence of age on natural and delayed healing of experimentally-induced gastric ulcers in rats.

This study aimed to investigate the effect of age on natural ulcer healing and delayed ulcer healing induced by nonsteroidal antiinflammatory drugs, using a rat model. Gastric ulcers were induced in young, adult, and aged rats using serosal or mucosal (kissing ulcers) application of acetic acid. Rats were treated with indomethacin 1 mg/kg/day subcutaneously or vehicle for two weeks. Ulcers were assessed by macroscopic and histological measurements of ulcer size. Ulcer induction was affected by age. Aged rats developed significantly smaller ulcers when induced by serosal application of acetic acid and significantly larger ulcers from mucosal application of acetic acid. However, measurements of ulcer size from both models showed no age-related differences in natural ulcer healing. Similarly, indomethacin-induced delayed gastric ulcer healing was not effected by age. We conclude that there are age-related differences in the development of gastric ulcers but there are no age-related differences in natural or delayed ulcer healing in rats.

Acetates↗

Characterization of an animal model of hepatic metastasis.

The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (10(6) cells in 1 mL). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible tumours with a diameter of 0.18 +/- 0.02 cm (mean +/- s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 +/- 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non-diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 +/- 0.14 cm3. Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 +/- 0.02 cm3 at day 10 to 0.22 +/- 0.24 cm3 by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 +/- 0.74 cm3 by day 19 (P = 0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 +/- 0.55 cm3 at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 +/- 0.006 cm3 first seen on day 10 increased to 0.05 +/- 0.06 cm3 by day 16, and to 0.25 +/- 0.20 cm3 by day 22 (P = 0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the non-diseased liver. Tumour blood flow, expressed as a percentage of normal liver blood flow, was 63.31 +/- 26.28% at day 10 and diminished to 27.91 +/- 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P = 0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases.

Animals↗

Sulindac and indomethacin inhibit formation of aberrant crypt foci in the colons of dimethyl hydrazine treated rats.

Aberrant crypt foci are microscopic lesions found in the colons of rodents treated with carcinogens, and in patients with premalignant colorectal conditions. They consist of single or multiple abnormal crypts and show cellular changes ranging from dysplasia to microscopic adenomacarcinoma. It is thought that these lesions represent the initial stages of the adenomacarcinoma path that results in the development of colorectal neoplasia. We have examined the effect of sulindac and indomethacin on the formation of aberrant crypt foci in rats treated with dimethylhydrazine (DMH). Aberrant crypt foci were induced in male Sprague-Dawley rats with two oral doses of dimethyl hydrazine at 25 mg/kg per dose. Rats were randomized to receive sulindac at 3 mg/kg (n = 20) or 10 mg/kg (n = 18) b.d., indomethacin at 1 mg/kg per day (n = 18) or 2 mg/kg per day (n = 19) or control (n = 37). Drug treatment was started on the day following the first dose of carcinogen and continued for 3 weeks. Colons were fixed flat overnight in 10% formalin and stained with 0.2%. Methylene Blue solution before being studied. There was a significant reduction in the number of aberrant crypt foci in rats treated with 10 mg/kg b.d., sulindac (P = 0.001) and indomethacin at 2 mg/kg per day (P = 0.0002). Sulindac, at 3 mg/kg b.d., and indomethacin, at 1 mg/kg per day, did not have a statistically significant effect (P = 0.089 and P = 0.052, respectively). None of the drug treatments affected the relative frequency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the growth and development of tumours in DMH treated rats. The current data suggest that one of the pathways of action of NSAID is to inhibit the formation of early preneoplastic lesions.

Animals↗

Inhibition of colon cancer precursors in the rat by sulindac sulphone is not dependent on inhibition of prostaglandin synthesis.

The non-steroidal anti-inflammatory drug, sulindac, inhibits the growth of colorectal tumours in animal models of colon cancer and causes regression of polyps in patients with familial adenomatous polyposis. The mechanism by which sulindac exerts this inhibitory effect is not known, but it has been postulated to be via the inhibition of prostaglandin synthesis. However, two recent studies have indicated that sulindac sulphone, the non-prostaglandin inhibiting metabolite of sulindac, may be important in tumour inhibition. In the present study, we examined the effect of sulindac sulphone on the formation of aberrant crypt foci, the earliest identifiable lesions in the development of colorectal cancer, in the rat colon. We have previously shown that sulindac causes a dose dependent inhibition of aberrant crypt formation in this model. Aberrant crypt foci were induced with two oral doses of 1,2-dimethyl hydrazine at 25 mg/kg per dose. Treatment with sulindac sulphone at either 10 mg/kg b.d., or 20 mg/kg, b.d., was started on the day following administration of the first carcinogen dose and was continued for 3 weeks. Colons were then removed and examined for aberrant crypt foci. Colonic crypts were visualized by staining the unsectioned colon in 0.2% methylene blue solution. There was a significant reduction in the number of aberrant foci in rats treated with sulindac sulphone at 20 mg/kg, b.d. (ANOVA, P = 0.0054). The mechanism by which non-steroidal anti-inflammatory drugs inhibit formation of aberrant crypt foci is not clear; however, these data suggest that it is not due to the inhibition of prostaglandin synthesis.

Animals↗