Polyamines regulate expression of the neoplastic phenotype in mouse skin.
Elevated polyamine levels are characteristic of many types of neoplastic cells and tissues. We demonstrate that in transgenic mice overexpressing ornithine decarboxylase in skin, changes in tissue polyamine levels, particularly putrescine, control the development and maintenance of the neoplastic phenotype. A specific inhibitor of the transgene, alpha-difluoromethylornithine (DFMO), reversibly blocked the appearance of squamous papillomas after carcinogen treatment. Furthermore, treatment of papilloma-bearing mice with DFMO caused rapid tumor regression, also in a reversible manner. Although the rate of apoptosis in papillomas was unaffected by acute DFMO treatment, tumor cell proliferation was rapidly decreased after drug treatment. Conversely, proliferation of normal epidermal keratinocytes was unaffected by DFMO treatment. The regulatory polyamine in this model appears to be putrescine, the immediate product of ornithine decarboxylase. These results demonstrate that elevated polyamine levels are required for both the development and maintenance of the neoplastic phenotype in skin.
Peralta Soler
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A
The Lankenau Medical Research Center, Wynnewood, Pennsylvania 19096, USA.
Gilliard
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Megosh
L
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George
K
K
O'Brien
T G
TG
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002291:Carcinoma, Papillary / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D004791:Enzyme Inhibitors; D011073:Polyamines; D013096:Spermine; D015127:9,10-Dimethyl-1,2-benzanthracene; D009955:Ornithine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine