POLYAMINES REGULATE EXPRESSION OF THE NEOPLASTIC PHENOTYPE IN MOUSE SKIN

Elevated polyamine levels are characteristic of many types of neoplast ic cells and tissues. We demonstrate that in transgenic mice overexpre ssing ornithine decarboxylase in skin, changes in tissue polyamine lev els, particularly putrescine, control the development and maintenance of the neoplastic phenotype, A specific inhibitor of the transgene, al pha-difluoromethylornithine (DFMO), reversibly blocked the appearance of squamous papillomas after carcinogen treatment. Furthermore, treatm ent of papilloma-bearing mice with DFMO caused rapid tumor regression, also in a reversible manner. Although the rate of apoptosis in papill omas 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. Th e regulatory polyamine in this model appears to be putrescine, the imm ediate product of ornithine decarboxylase, These results demonstrate t hat elevated polyamine levels are required for both the development an d maintenance of the neoplastic phenotype in skin.