Effect of plyamine oxidase inhibition on the colonic malignant transformation process induced by 1.2-dimethylhydrazine

Allan G. Halline, Pradeep K. Dudeja, Russell F. Jacoby, Xavier Llor, Ba Bie Teng, Lokendra N. Chowdhury, Nicholas Davidson, Thomas A. Brasitus

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Recent studies of colon adenocarcinomas in humans and experimentally induced colonic tumors in rodents have demonstrated selective elevations in the level of N1-acetylspermindine in these malignant tissues. The exact relationship fo 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-dimethylhydrazube (DNG; 20mg/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 (25 mg/kg body wt/week), a specific inhibitor of polyamine oxidase, unitil they were killed. Animals were killed after 15 weeks of DMH treatment and polyamine levels as well as the activites of polyamine oxidase, ornithine decarboxylase and spermidine-N1-acetyltransferase were measured and compared in rat proximal and distal colonic mucosa of each 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 form DMH ± MDL 72527 were analyzed for K-ras mutations. The tesults 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 fo colonic N1-acetylspermidine and sinificantly 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%) (iv) however, analysis of the K-ras-mutated and nonmutated 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.

Original languageEnglish
Pages (from-to)2127-2132
Number of pages6
JournalCarcinogenesis
Volume11
Issue number12
DOIs
StatePublished - Dec 1990

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