Effects of the oil and mucilage from flaxseed (linum usitatissimum) on gastric lesions induced by ethanol in rats.

The anti-ulcer activity of the oil and mucilage obtained from flaxseed (Linum usitatissimum) was evaluated in a rat model of ethanol-induced gastric ulcer. Our results show that pretreatment of rats with flaxseed oil and flaxseed mucilage significantly reduced the number and length of gastric ulcers induced by ethanol. Flaxseed oil was more effective than flaxseed mucilage in reducing the number of ulcers. The reduction in ulcer severity (cumulative length in mm) provided by an oral dose of flaxseed oil (5 ml/kg) was more prominent than that obtained by ranitidine (50 mg/kg). This study indicates that both flaxseed oil and flaxseed mucilage can provide a cytoprotective effect against ethanol-induced gastric ulcers in rats.

Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors.

Variant liver oestrogen receptor transcripts in hepatocellular carcinoma are associated with aggressive clinical course and unresponsiveness to tamoxifen. To evaluate the impact on survival and on tumour growth of megestrol (progestin drug acting at post-receptorial level) we enrolled 45 patients with HCC characterized by variant liver oestrogen receptors in a prospective, randomized study with megestrol vs. placebo. Presence of variant oestrogen receptors was determined by RT/PCR. 24 patients were randomized to no treatment and 21 to therapy with megestrol 160 mg day(-1). Results were analysed by Kaplan-Meier and Cox methods. Survival of hepatocellular carcinoma characterized by variant oestrogen receptors was extremely poor (median survival 7 months); megestrol significantly improved survival (18 months) (P = 0.0090). Tumour growth at one year was significantly slowed down in megestrol-treated patients (P = 0.0212). Bilirubin levels, presence of portal thrombosis, HBV aetiology and treatment were identified at univariate analysis as factors significantly associated with survival; at multivariate analysis, only megestrol therapy (P = 0.0003), presence of HBV infection (P = 0.0009) and presence of portal vein thrombosis (P = 0.0051) were factors independently related with survival. (1) Megestrol slows down the aggressive tumour growth of patients with hepatocellular carcinoma characterized by variant estrogen receptors and (2) is also able to favourably influence the course of disease, more than doubling median survival.

Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease.

Variant estrogen receptors may be found in hepatocellular carcinoma and may influence its natural history. Because it is not known whether their occurrence is an early or a late event during the course of chronic liver disease or whether they cluster in some subgroups of patients, we investigated a series of patients in different stages of chronic liver disease. One hundred eleven consecutive patients were studied for variant estrogen receptor transcripts by reverse-transcription polymerase chain reaction of RNA extracted from liver biopsy specimens. In chronic active hepatitis, variant estrogen receptor transcripts were coexpressed with wild-type significantly more often in men than in women (P = .029) and in hepatitis B surface antigen (HBsAg)-positive subjects than in subjects positive for antibody to hepatitis C virus (P = .0006). In hepatocellular carcinoma, again in men (P = .004) and in HBsAg-positive patients (P = .0015), the variant estrogen receptor transcript was overexpressed or remained the only one expressed. Patients with liver cell dysplasia presented with the same estrogen receptor pattern than patients with hepatocellular carcinoma. This further reinforces the significance of liver cell dysplasia as a preneoplastic condition. The significantly higher occurrence of variant estrogen receptor in men (especially in HBsAg-positive men) already at an early stage of disease, like chronic active hepatitis, suggests that the alteration of estrogen receptors, favoring uncontrolled proliferation and development of hyperplasia, might constitute a prominent mechanism facilitating neoplastic transformation especially in men.

Type of estrogen receptor determines response to antiestrogen therapy.

Failure of tamoxifen treatment for unresectable hepatocellular carcinomas (HCCs) might be caused by variant estrogen receptors (ERs) in some of these tumors. We therefore planned a study in which antihormonal therapy was done with 80 mg/day tamoxifen or 160 mg/day megestrol according to the presence of wild-type or exon 5-deleted variant ER transcripts. Growth rate (evaluated by MRI) of HCCs characterized by variant ER transcripts was 4 times more rapid than that of HCCs with wild-type ERs. Tumor volume in all patients with wild-type ERs was halved after 9 months of tamoxifen treatment, whereas megestrol in patients with variant ERs only slowed down tumor growth. Choosing antihormonal treatment according to the presence of wild-type or variant ERs in the tumor definitely improves the response rate to tamoxifen; in patients with tumors bearing variant ERs, megestrol causes only a temporary inhibition of tumor growth.

Identification of subjects at risk for colorectal carcinoma through a test based on K-ras determination in the stool.

BACKGROUND & AIMS: The gold standard for screening for colorectal carcinoma is colonoscopy. The aim of this study was to compare endoscopic results with those obtained using the noninvasive screening test of K-ras determination in the stool in a large population of patients undergoing colonoscopy. METHODS: Two hundred thirty consecutive patients were studied by K-ras amplification on stool-derived DNA using polymerase chain reaction and oligomer-specific hybridization. RESULTS: Wild-type K-ras was amplified in 103 of 230 patients (44.8%), the rate of amplification being directly proportional to the presence of an organic disease of the intestine characterized by hyperproliferating mucosa. In 30 of these 103 patients (29.1%), a K-ras mutation was found. Four of 5 with early colorectal carcinoma, all who had K-ras mutations in the tumor, were identified. In first-degree relatives of patients with colorectal carcinoma, all subjects either carrying adenomas > 1 cm in diameter or multiple smaller adenomas were identified. In patients with inflammatory bowel disease, the test identified the only patient with neoplastic transformation. CONCLUSIONS: The sensitivity and specificity of K-ras determination on stool-derived DNA in patients with colorectal carcinoma, in first-degree relatives of patients with colorectal carcinoma, and in patients with inflammatory bowel disease support the opportunity of a large-scale trial to validate its use as a screening test.

Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma.

The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a significantly higher proportion than females. Liver estrogen receptors increase when HCC develops in males; however, these tumors usually respond poorly to antiestrogens. We have, therefore, hypothesized that, similar to breast cancer, estrogen receptors in males with HCC may be mutated. Variant estrogen receptor transcripts (lacking exon 5 of the hormone binding domain) were investigated by reverse transcription-PCR in 14 patients (7 males and 7 females) with HCC. While females mostly displayed the wild-type transcript (both in peritumoral and in tumor liver tissue), males showed both transcripts in the cirrhotic tissue and almost only the variant in the tumor. As the variant ER transcripts when translated could give rise to truncated receptors still able to constitutively activate transcription, they may be key factors in favoring deregulated proliferation in the male liver.

Effects of dopamine agonists and antagonists on gastric acid secretion and stress responses in rats.

The dopamine agonists and promoters bromocriptine, bupropion, and p-hydroxymethylphenidate (a peripherally acting methylphenidate analog) reduced basal gastric acid secretion in rats, while the dopamine antagonists haloperidol, pimozide and metoclopramide augmented gastric acid output. Stress ulcer formation and plasma corticosterone levels were markedly reduced by l-dopa given either intraperitoneally or intracerebroventricularly as well as by intraperitoneally administered p-hydroxymethylphenidate. Domperidone, a peripheral dopamine receptor blocker, produced variable effects on stress responses, indicating a wider spectrum of action than hitherto realized for this compound. The results strongly support a role for both central and peripheral dopaminergic activity in reducing the pathological consequences of exposure to stress.

L-deprenyl attenuates stress ulcer formation in rats.

Both intraperitoneal and intracerebroventricular (i.c.v.) administration of the monoamine oxidase-B inhibitor L-deprenyl markedly attenuated restraint stress-induced gastric ulcers in rats. L-Deprenyl given i.c.v. attenuated stress ulcers in microgram doses and virtually abolished ulcer formation at a dose of 2.0 micrograms. These data suggest that intact or augmented central dopaminergic function may be an essential component of gastric mucosal protection.

Capsaicin effects on stress pathology and gastric acid secretion in rats.

The effects of capsaicin on stress ulcer formation, plasma corticosterone levels and gastric acid secretion were examined in rats. Capsaicin desensitization did not affect restraint stress ulcer formation but was associated with markedly elevated corticosterone levels, even in non-stressed rats. Acute, orally administered capsaicin augmented ulcer formation only if its administration was followed immediately by restraint stress. Delays of 1, 2, or 3 h between drug administration and stress produced ulceration comparable to control values. Capsaicin did not affect basal (non-stimulated) gastric acid secretion but substantially decreased pentagastrin-stimulated acid output.