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.