Transgenic Mice with Activated Polyamine Catabolism due to Overexpression of Spermidine/Spermine N-Acetyltransferase Show Enhanced Sensitivity to the Polyamine Analog, N,N-Diethylnorspermine

We have recently generated transgenic mice in which polyamine catabolism has been activated by overexpressing the rate-limiting enzyme of polyamine catabolism, spermidine/ spermine N-acetyltransferase (SSAT). These animals have now been tested for their sensitivity to the polyamine analog N,N-diethylnorspermine (DENSPM), which is currently undergoing Phase I clinical trial. The analog is known for its ability to potently induce SSAT. Treatment for 4 days with a daily dose (125 mg/kg) of analog caused profound changes in polyamine metabolism in the transgenic animals. Liver SSAT activity was increased by approximately 800-fold while hepatic mRNA increased only 4-fold. Putrescine pools increased while spermidine and spermine pools nearly disappeared, resulting in a compensatory increase in ornithine decarboxylase activity. Similar but less profound changes were also seen in other tissues (spleen, intestine, and skin). This treatment also resulted in a 50% mortality in the transgenic animals, with no apparent histopathological changes in major organs. Nontransgenic animals exhibited no toxicity, and tissue SSAT activity was unchanged or only moderately increased. Polyamine pools were only slightly altered. Greater analog toxicity in transgenic animals may be attributable to higher tissue levels of DENSPM facilitated by SSAT-mediated decreases in spermidine and spermine. To further confirm the enhanced sensitivity of the transgenic animals to the analog, groups of nontransgenic and transgenic animals were subjected to daily injections with DENSPM. On average, transgenic mice died ;3 days earlier than their nontransgenic litter-mates. The findings indicate a contributing role for SSAT in whole animal toxicity by SSATinducing polyamine analogs. The polyamine biosynthetic pathway has long been considered a worthwhile target for cancer chemotherapy. However, despite the impressive preclinical activity of inhibitors of ornithine decarboxylase (ODC), the rate-controlling enzyme of the biosynthesis, the results of clinical trials have so far not met expectations (Jänne et al. 1991; Porter et al. 1992; Kramer, 1996). Certain of these inhibitors are currently being reevaluated as chemopreventive agents (Creaven et al. 1993; Love et al. 1993), and promising results are emerging. On the basis of impressive preclinical findings (Regenass et al. 1992, 1994), a newly identified inhibitor of another biosynthetic enzyme, S-adenosylmethionine decarboxylase (AdoMetDC), is now being evaluated in patients with solid