Document Detail

Effect of polyamine oxidase inhibition on the colonic malignant transformation process induced by 1,2-dimethylhydrazine.
MedLine Citation:
PMID:  2265465     Owner:  NLM     Status:  MEDLINE    
Recent studies of colon adenocarcinomas in humans and experimentally induced colonic tumors in rodents have demonstrated selective elevations in the level of N1-acetylspermidine in these malignant tissues. The exact relationship of these alterations in acetylated polyamine levels to the malignant transformation process, however, remains unclear. In order to clarify this issue, rats were given s.c. injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt/week) or diluent for up to 26 weeks. After 10 weeks of carcinogen treatment, one-half of the animals in each group were also concomitantly given i.p. injections of MDL 72527 (20 mg/kg body wt/week), a specific inhibitor of polyamine oxidase, until they were killed. Animals were killed after 15 weeks of DMH treatment and polyamine levels as well as the activities of polyamine oxidase, ornithine decarboxylase and spermidine-N1-acetyltransferase were measured and compared in rat proximal and distal colonic mucosa of each group. Polyamine levels were also assessed in each of these groups after 26 weeks of treatment with this carcinogen +/- MDL 72527. In addition, in view of recent studies that have indicated that polyamines may influence certain oncogenes in human colonic carcinoma cells, tumors from DMH +/- MDL 72527 were analyzed for K-ras mutations. The results of these experiments demonstrated for the first time that: (i) MDL 72527 was a specific inhibitor of polyamine oxidase in normal and malignant colonic tissue; (ii) concomitant administration of this agent with DMH enhanced the elevation of colonic N1-acetylspermidine and significantly reduced the mean colonic tumor burden, as assessed by total tumor area per rat, produced by this carcinogen alone; (iii) analysis of K-ras mutations revealed a similar incidence (62-69%) in adenocarcinomas for both groups (+/- MDL 72527); (iv) however, analysis of the K-ras-mutated and non-mutated tumors revealed that in both carcinogen-treated groups (+/- MDL 72527), tumors with such mutations were smaller than their counterparts without such genetic alterations. Moreover, MDL 72527 reduced the average size of tumors, with and without such mutations, to a similar extent.
A G Halline; P K Dudeja; R F Jacoby; X Llor; B B Teng; L N Chowdhury; N O Davidson; T A Brasitus
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Carcinogenesis     Volume:  11     ISSN:  0143-3334     ISO Abbreviation:  Carcinogenesis     Publication Date:  1990 Dec 
Date Detail:
Created Date:  1991-02-12     Completed Date:  1991-02-12     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2127-32     Citation Subset:  IM    
Department of Medicine, University of Chicago, IL 60637.
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MeSH Terms
Acetyltransferases / analysis
Adenocarcinoma / chemically induced,  prevention & control*
Base Sequence
Carcinogens / pharmacology*
Colon / chemistry
Colonic Neoplasms / chemically induced,  prevention & control*
Dimethylhydrazines / pharmacology*
Genes, ras / genetics
Molecular Sequence Data
Neoplasms, Experimental*
Ornithine Decarboxylase / analysis
Oxidoreductases Acting on CH-NH Group Donors / analysis,  antagonists & inhibitors*
Polymerase Chain Reaction
Putrescine / analogs & derivatives*,  pharmacology
Rats, Inbred Strains
Grant Support
Reg. No./Substance:
0/Carcinogens; 0/Dimethylhydrazines; 110-60-1/Putrescine; 540-73-8/1,2-Dimethylhydrazine; 93565-01-6/MDL 72527; EC 1.5.-/Oxidoreductases Acting on CH-NH Group Donors; EC 1.5.3.-/polyamine oxidase; EC 2.3.1.-/Acetyltransferases; EC N-acetyltransferase; EC Decarboxylase

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