Weeks C E, Herrmann A L, Nelson F R, Slaga T J
Proc Natl Acad Sci U S A. 1982 Oct;79(19):6028-32. doi: 10.1073/pnas.79.19.6028.
The role of ornithine decarboxylase (OrnDCase, EC 4.1.1.17) and of the polyamines [putrescine (Put), spermidine (Spd), and spermine (Spm)] in mouse skin tumor promotion was investigated by the use of alpha-difluoromethylornithine (CHF2-Orn), an enzyme-activated irreversible inhibitor of OrnDCase. 12-O-Tetradecanoylphorbol 13-acetate (TPA), mezerein, and ethyl phenylpropiolate (EPP) were employed as complete, stage II specific, and nonpromoting agents, respectively. TPA and mezerein, but not EPP, provided for a dose-dependent increase in tissue Put accumulation. The Put level in papillomas developed by TPA (2 micrograms) treatment was approximately equal to 15-fold higher than that of the surrounding skin tissue; Spd accumulation was 2- to 3-fold greater in the papillomas. Put administered (intraperitoneally) with TPA greatly enhanced papilloma yield. CHF2-Orn, given orally or intraperitoneally, abolished the TPA-induced OrnDCase activity and Put accumulation in mouse epidermis. The reduction of polyamine accumulation by CHF2-Orn was directly proportional to reduction of tumor size. CHF2-Orn administered in a two-stage (TPA-mezerein) promotion protocol [Slaga, T. J., Fischer, S. M., Nelson, K. G. & Gleason, G. L. (1980) Proc. Natl. Acad. Sci. USA 77, 3659-3663; Slaga, T. J., Klein-Szanto, A. J. P., Fischer, S. M., Weeks, C. E., Nelson, K. & Major, S. (1980) Proc. Natl. Acad. Sci. USA 77, 2251-2254] reduced tumor size, inhibited by 65-70% the number of papillomas per mouse, and decreased by 40% the percentage of mice with tumors when given with the stage II agent mezerein. CHF2-Orn provided considerably less effect on tumorigenesis when administered with the TPA portion of the protocol, and CHF2-Orn did not inhibit the induction of dark basal keratinocytes by TPA. Based on our results with CHF2-Orn, we suggest that regulation of polyamine biosynthesis, particularly Put, is a critical factor in stage II promotion.
通过使用α-二氟甲基鸟氨酸（CHF2-Orn），一种鸟氨酸脱羧酶（OrnDCase，EC 4.1.1.17）的酶激活不可逆抑制剂，研究了鸟氨酸脱羧酶和多胺[腐胺（Put）、亚精胺（Spd）和精胺（Spm）]在小鼠皮肤肿瘤促进中的作用。分别使用12-O-十四烷酰佛波醇13-乙酸酯（TPA）、卫矛醇和苯丙炔酸乙酯（EPP）作为完全、II期特异性和非促进剂。TPA和卫矛醇能使组织中Put积累呈剂量依赖性增加，而EPP则不能。经TPA（2微克）处理产生的乳头状瘤中的Put水平比周围皮肤组织中的Put水平高约15倍；乳头状瘤中Spd的积累量则高2至3倍。与TPA一起（腹腔内）给予Put可大大提高乳头状瘤的产量。口服或腹腔内给予CHF2-Orn可消除TPA诱导的小鼠表皮中的OrnDCase活性和Put积累。CHF2-Orn对多胺积累的减少与肿瘤大小的减少直接成比例。在两阶段（TPA-卫矛醇）促进方案中给予CHF2-Orn[斯拉加，T. J.，菲舍尔，S. M.，纳尔逊，K. G. & 格利森，G. L.（1980年）美国国家科学院院刊77，3659 - 3663；斯拉加，T. J.，克莱因-桑托，A. J. P.，菲舍尔，S. M.，威克斯，C. E.，纳尔逊，K. & 梅杰，S.（1980年）美国国家科学院院刊77，2251 - 2254]可减小肿瘤大小，当与II期试剂卫矛醇一起给予时，每只小鼠的乳头状瘤数量可被抑制65 - 70%，有肿瘤的小鼠百分比可降低40%。当与方案中的TPA部分一起给予时，CHF2-Orn对肿瘤发生的影响要小得多，并且CHF2-Orn不会抑制TPA诱导的暗基底角质形成细胞。基于我们使用CHF2-Orn的结果，我们认为多胺生物合成的调节，特别是Put的调节，是II期促进中的一个关键因素。
