Role of Ornithine Decarboxylase and Polyamines in Camostate (Foy-305)-Induced Pancreatic Growth in Rats

Löser, Chr.; Fölsch, U.R.; Cleffmann, Ulrike; Nustede, R.; Creutzfeldt, W.

doi:10.1159/000199867

Cited by 24 publications

(19 citation statements)

References 16 publications

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“…The pancreas is the richest source of the polyamine spermidine in the mammalian body (10). Various hormones, such as cholecystokinin and its analogue caerulein, enhance pancreatic polyamine biosynthesis (10,19).…”

Section: Discussionmentioning

confidence: 99%

“…Various hormones, such as cholecystokinin and its analogue caerulein, enhance pancreatic polyamine biosynthesis (10,19). On the other hand, specific inhibition of ornithine decarboxylase by ␣-difluoromethylornithine not only prevented the accumulation of putrescine and spermidine but also retarded pancreatic growth (20).…”

Section: Discussionmentioning

confidence: 99%

“…tion of ornithine decarboxylase leads to an accumulation of putrescine associated with the initiation of pancreatic growth, whereas intracellular spermidine accumulation apparently is needed for the maintenance of the growth (10,(19)(20)(21)(22)(23). However, determinations of the exact functions of the polyamines in the pancreas or in any mammalian tissues are only tentative.…”

Section: Discussionmentioning

confidence: 99%

“…In regard to polyamines, the pancreas occupies a very special position among mammalian organs and tissues. The pancreas seems to contain the highest concentration of spermidine in the mammalian body (10). Therefore, the aim of our study was to generate a transgenic rat line expressing the mouse SSAT gene under the control of the metallothionein I promoter to elucidate the roles of the higher polyamines in the pancreas.…”

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confidence: 99%

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Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Alhonen

Parkkinen²,

Keinänen³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine͞spermine N 1 -acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N 1 -acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N 1 ,N 2 -bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N 1 ,N 11 -diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N 1 ,N 11 -diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.I ntracellular polyamine levels are tightly maintained by a number of mechanisms, suggesting their importance for cell function. This polyamine homeostasis is controlled by their biosynthesis, interconversion, catabolism, secretion, and uptake. Polyamine biosynthesis is regulated by the activities of ornithine and S-adenosylmethionine decarboxylases. Overexpression of ornithine decarboxylase in transgenic rodents affected spermatogenesis (1, 2), rendered animals more resistant to chemically or electrically induced seizure activity (3) and to ischemic insults (4), and enhanced skin papilloma formation (5). However, the activation of polyamine biosynthesis caused by overexpression of ornithine decarboxylase did not result in enhanced accumulation of the higher polyamines spermidine and spermine. Polyamine catabolism is controlled by the activity of spermidine͞spermine N 1 -acetyltransferase (SSAT; refs. 6 and 7). The acetylated products are oxidized further by the polyamine oxidase (PAO) to spermidine and putrescine. We recently generated transgenic mouse lines with ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Alhonen

Parkkinen²,

Keinänen³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…It is well known that the polyamine metabolism is essentially involved in normal and adaptive pancreatic growth in rats [25, 26, 27, 28]. α-Difluoromethylornithine (DFMO) is a potent specific inhibitor of ornithine decarboxylase (ODC) which is the key enzyme of intracellular polyamine synthesis [5].…”

Section: Introductionmentioning

confidence: 99%

Effects of Insulin-Like Growth Factor I on Growth and Polyamine Metabolism in Various Organs in Rats

Höpfner¹,

Berger²,

Fölsch³

et al. 2002

Digestion

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Background/Aim: Human insulin-like growth factor I (IGF-I) is known to be the mediator of growth hormone dependent proliferation and is responsible for growth-promoting effects in the gastrointestinal tract. Polyamines play an essential role in cell growth and differentiation. The aim of the present study was to investigate the growth-promoting potency of IGF-I in various organ systems simultaneously in rats and the potential role of the polyamine metabolism during IGF-I-induced gastrointestinal growth. Methods: Based on results of initial dose-response studies, male Wistar rats (150 g) were either treated by subcutaneous injections with (1) IGF-I (1 × 1,000 µg/kg/24 h); (2) IGF-I plus α-difluoromethylornithine (3 × 300 mg i.p./kg/24 h plus 2% in drinking water), a specific inhibitor of intracellular polyamine de novo synthesis, or (3) saline (controls). 9–10 animals per group were sacrificed after 5 days of treatment. Results: IGF-I caused a significant (p < 0.005) increase in the weight of small intestine and spleen due to hyperplasia in the small intestine and hypertrophy and hyperplasia in the spleen, while no trophic effects could be observed in stomach or pancreas. The amylase concentration in the pancreas was increased. Simultaneously administered α-difluoromethylornithine significantly (p < 0.005) abolished the IGF-I-induced trophic effects in small intestine and spleen. Conclusions: These data reveal different trophic effects of IGF-I in various organ systems: while significant growth stimulation was found in small intestine and spleen, no proliferation was seen in pancreas and stomach. Polyamines obviously play an important role in IGF-I-mediated gastrointestinal growth.

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An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Phanstiel

2017

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.

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Role of Ornithine Decarboxylase and Polyamines in Camostate (Foy-305)-Induced Pancreatic Growth in Rats

Cited by 24 publications

References 16 publications

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Effects of Insulin-Like Growth Factor I on Growth and Polyamine Metabolism in Various Organs in Rats

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

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