Abstract
We have recently generated transgenic mice in which polyamine catabolism has been activated by overexpressing the rate-limiting enzyme of polyamine catabolism, spermidine/spermineN1 -acetyltransferase (SSAT). These animals have now been tested for their sensitivity to the polyamine analogN1,N11-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 SSAT-inducing polyamine analogs.
Footnotes
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Send reprint requests to: Dr. Carl W. Porter, Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263. E-mail: porter{at}sc3101.med.buffalo.edu
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↵1 Current Address: Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263. E-mail: porter{at}sc3101.med.buffalo.edu
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This work was supported in part by the CA-65942 and CA-22153 US National Cancer Institute, National Institutes of Health, by the Academy of Finland and by Human Frontier Science Program.
- Abbreviations:
- DENSPM
- N1,N11-diethylnorspermine
- SSAT
- spermidine/spermineN1-acetyltransferase
- ODC
- ornithine decarboxylase
- AdoMetDC
- S-adenosylmethionine decarboxylase
- Received September 30, 1998.
- Accepted December 18, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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