Mechanisms of tumor promoter-induced refractory state and enhanced state for the tumor promoter-caused ornithine decarboxylase induction

Research Project

Project/Area Number	62571029
Research Category	Grant-in-Aid for General Scientific Research (C)
Allocation Type	Single-year Grants
Research Field	応用薬理学・医療系薬学
Research Institution	Keio University
Principal Investigator	NAKADATE Teruo School of Medicine, Keio University, 医学部, 講師 (60112695)
Co-Investigator(Kenkyū-buntansha)	SASAKAWA Nobuyuki School of Medicine, Keio University, 医学部, 助手 (20187107)
Project Period (FY)	1987 – 1988
Project Status	Completed (Fiscal Year 1988)
Budget Amount *help	¥2,100,000 (Direct Cost: ¥2,100,000) Fiscal Year 1988: ¥400,000 (Direct Cost: ¥400,000) Fiscal Year 1987: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywords	Tumor promoter / Ornithine decarboxylase / TPA / Palmitoylcarnitine / マウス培養表皮細胞 / 腫瘍プロモーション / 培養表皮細胞 / C-キナーゼ
Research Abstract	The 12-O-tetradecanoylphorbol-13-acetate(TPA), a tumor promoter, -caused refractory state and enhanced state for the TPA-caused epidermal ornithine decarboxylase (ODC) induction in mouse skin were investigated in order to clear the relationship between epidermal ODC induction and skin tumor promotion. 1. When a single topical application of TPA was performed 12-24 hr before the 2nd application, ODC induction by the 2nd application of TPA was markedly suppressed (refractory state). Meanwhile, at intervals of 96 hr between lst and 2nd application, the ODC activity induced by second application of TPA was higher (enhanced state) than the activity induced by the single application. 2. When various antitumor promoting agents were applied concurrently with the lst TPA application, the ODC induction in the refractory state was restored only by palmitoylcarnitine, a protein kinase C inhibitor. 3. Pretreatment of mice with TPA 12 or 96 hr defore the 2nd TPA application resulted in the reduction or the increase in the V_<max> values of ODC both for ornithine and pyridoxal-5'-phosphate. Palmitoylcarnitine restored these reduced V_<max> values. 4. The TPA-induced refractory state and the enhanced state for ODC induction appear to result from the changes in the protein kinase C activities caused by TPA. However, it is not known whether such changes in the protein kinase C activities are the major causes for the TPA-induced refractory and/or enhanced state for ODC induction. 5. TPA-induced refractory state for TPA-caused ODC induction was observed in cultured mouse epidermal cells. 6. Application of TPA at intervals of 24 hr, which induces the refractory state for ODC induction, was not necessarily more unfavorable for the formation of tumors in the experiments of skin tumor promotion than TPA application at intervals of 72-96 hr, which induces the enhanced state for ODC induction.