Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.17 (ornithine decarboxylase)
 6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male weanling rats of the Charles River Sprague-Dawley strain were exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the water for 3 months at the concentration of 75 ml/litre. Other real or potential risk factors were administered, alone or in combination with MNNG. When MNNG was administered in combination with NaCl, bile acids, aspirin or BHA, forestomach tumours were enhanced. MNNG-induced tumours were inhibited by selenium or by difluoromethylornithine, an ornithine decarboxylase inhibitor. BHA alone caused forestomach tumours. When BHA was administered by dietary means or by gavage, alone or in combination with MNNG, the gavage method resulted in greater tumorigenesis than dietary exposure. This increase was associated with increased [3H]thymidine labelling of forestomach epithelium and increased hyperplasia. Oesophageal carcinogenesis induced by methylbenzylnitrosamine (MBN) was enhanced by zinc deficiency, alcohol and 13-cis-retinoic acid. Zinc deficiency also resulted in oesophageal tumours in rats exposed to the hepatocarcinogen dimethylnitrosamine. Riboflavin deficiency injured oral and oesophageal epithelium and increased sensitivity to MBN-induced oesophageal tumours.
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PMID:Gastric and oesophageal carcinogenesis: models for the identification of risk and protective factors. 310 Apr 3

Antizyme (AZ) is known to be a regulator of polyamine metabolism that inhibits ornithine decarboxylase activity and polyamine transport, thus restricting polyamine levels. Transgenic mice with AZ expression targeted to the basal cell layer of the forestomach epithelium by the keratin 5 promoter were used to investigate whether AZ overexpression inhibited uncontrolled cell proliferation in zinc-deficient (ZD) mice and reduced their susceptibility to forestomach carcinogenesis by N-nitrosomethylbenzylamine (NMBA). Four-week-old keratin 5/AZ and wild-type (Wt) littermates were placed on ZD or zinc-sufficient (ZS) diets to form four groups: ZD:AZ, ZD:Wt, ZS:AZ, and ZS:Wt. After 5 weeks, 27-45 mice in each group were treated twice with NMBA and sacrificed 14 weeks later. Independent of zinc intake, AZ mice had significantly lower forestomach tumor incidence and tumor multiplicity than respective Wt littermates (P < 0.001): 21% of ZD:AZ versus 76% of ZD:Wt mice and 3% of ZS:AZ versus 33% of ZS:Wt mice developed tumors. Spermidine content was reduced in NMBA-treated ZD:AZ forestomachs. Zinc deficiency increased the forestomach cell proliferation in Wt mice, but this effect was blocked by AZ. Conversely, apoptosis was substantially higher in control and NMBA-treated ZD:AZ than respective ZD:Wt forestomachs. The restored ZD:AZ forestomach epithelium displayed strong expression of Bax, a proapoptotic protein, and weak staining of cyclin D1 and its catalytic partner Cdk4, key regulatory proteins controlling G(1) to S progression. In contrast, proliferative ZD:Wt forestomach showed strong expression of Bcl-2, an antiapoptotic protein, and overexpression of cyclin D1/Cdk4. Treatment of ZD:Wt mice with alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase, had similar results to AZ in reducing tumor incidence, spermidine content, decreasing cell proliferation, and increasing apoptosis. These results demonstrate that AZ may act as a tumor suppressor gene stimulating apoptosis and restraining cell proliferation, thereby inhibiting forestomach tumor development. Although effects of AZ on functions other than polyamine metabolism are possible, alterations in polyamines are the most likely explanation for the reduction in tumors, supporting the use of strategies to modulate polyamine levels for cancer chemoprevention in individuals at high risk of developing malignancies of the gastrointestinal tract.
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PMID:Antizyme overexpression in transgenic mice reduces cell proliferation, increases apoptosis, and reduces N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. 1287 89