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Transformed cell

Fig. 9. Proposed model for Helicobacter py lowi-induced transformation of gastric epithelial cells. H. pylori infection results in an increase in SMO/PAOh1 mRNA, protein, and oxidase activity. The resulting H2O2 damages DNA, which, if the damage is sufficient, can cause apop-tosis or has the potential to lead to genetic mutation. If such mutations produce a growth or survival advantage, the potential for neoplastic transformation exists.

Transformed cell

Fig. 9. Proposed model for Helicobacter py lowi-induced transformation of gastric epithelial cells. H. pylori infection results in an increase in SMO/PAOh1 mRNA, protein, and oxidase activity. The resulting H2O2 damages DNA, which, if the damage is sufficient, can cause apop-tosis or has the potential to lead to genetic mutation. If such mutations produce a growth or survival advantage, the potential for neoplastic transformation exists.

have similar effects. Chu et al. have demonstrated that glutathione peroxidase 1 and 2 double knockout mice have an increased incidence of microflora-associated intestinal cancers that correlate with increased inflammation subsequent to peroxidative stress (14 4). If it is ultimately found that aberrant SMO/PAOh1 expression is directly associated with carcinogenic transformation, it would certainly point to the oxidase as a target for chemopreventive therapy.

6. Summary

The last few years have seen a dramatic increase in studies enhancing our knowledge of the regulation, function, and importance of the polyamine catabolic pathways. Instead of a single mammalian catabolic pathway regulated by SSAT, there exist at least two pathways by which spermine can be catabolized: the classical S S AT/PAO pathway and the direct catalysis of spermine by SMO/PAOh1. Although the precise interplay between these two pathways remains to be elucidated, clearly they are critical to the maintenance of normal polyamine homeostasis and have the potential to be dysregulated in various disease states. The emphasis of our group and others has been to understand the role that polyamine catabolism plays in the response of cells to the antitumor polyamine analogs, thus improving on our ability to target these pathways for therapeutic advantage. As is evident from the studies cited, a considerable body of work has amassed toward the goal of understanding the molecular mechanisms by which the major players in polyamine catabolism are re gulated.

It is now clear that induction of polyamine catabolism by specific analogs directly contributes to the cellular response caused by those agents, and that the response can be both cell- and tumor type-specific. The search for agents to exploit these responses is both active and ongoing. The recent finding demonstrating that increased SMO/PAOhl activity may be involved in the etiology of a cancer of epithelial origin opens up an entirely new area that may lead to effective chemopreventive strategies. With a strong foundation of data on which to build, the coming years mark exciting times for both the study and exploitation of polyamine catabolism for disease intervention.


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