Luk G D, Zhang S Z, Hamilton S R
Department of Medicine, Wayne State University School of Medicine, Detroit, MI.
J Natl Cancer Inst. 1989 Mar 15;81(6):421-7. doi: 10.1093/jnci/81.6.421.
During azoxymethane (AOM)-induced colonic carcinogenesis in rats, biphasic induction of ornithine decarboxylase (ODC) activity occurs in the colonic mucosa. The relative contributions of these two phases of ODC induction to the carcinogenesis process were examined by studying the effects of the specific ODC inhibitor, difluoromethylornithine (DFMO), administered during either the initial phase of ODC increase or during both phases continuously. The effects of 1% and 0.25% DFMO administered continuously were also compared. Continuous oral administration of DFMO at 1% (approximately 8 mg/g body wt/wk) and 0.25% (approximately 2 mg/g body wt/wk) produced 93% inhibition of ODC induction by AOM in the right and left colons throughout the study. Despite suppression of ODC activity to near-normal levels, colon tumor incidence at 26 weeks in the right colon was not affected by either initial-phase or continuous administration of DFMO. In contrast, tumor incidence in the left colon was reduced from 35% to 5% by DFMO given continuously at doses of both 1% and 0.25% over the entire 26 weeks (P less than .05). No significant reduction in left colon tumor incidence resulted from the short initial 11-week course of DFMO although the tumor incidence was reduced (15% vs. 35%). Results suggest that the second ("post-initiation") phase of ODC induction may be of particular importance in carcinogenesis.
在大鼠由氧化偶氮甲烷（AOM）诱导的结肠癌发生过程中，结肠黏膜中鸟氨酸脱羧酶（ODC）活性呈双相诱导。通过研究在ODC活性增加的初始阶段或两个阶段持续给予特异性ODC抑制剂二氟甲基鸟氨酸（DFMO）的效果，来检测这两个阶段的ODC诱导对致癌过程的相对贡献。还比较了持续给予1%和0.25% DFMO的效果。在整个研究过程中，持续口服1%（约8 mg/g体重/周）和0.25%（约2 mg/g体重/周）的DFMO可使AOM诱导的右半结肠和左半结肠ODC诱导受到93%的抑制。尽管ODC活性被抑制至接近正常水平，但右半结肠在26周时的结肠肿瘤发生率并未受到DFMO初始阶段给药或持续给药的影响。相比之下，在整个26周内持续给予1%和0.25%剂量的DFMO可使左半结肠的肿瘤发生率从35%降至5%（P<0.05）。尽管肿瘤发生率有所降低（15%对35%），但在最初11周短期给予DFMO并未使左半结肠肿瘤发生率显著降低。结果表明，ODC诱导的第二个（“启动后”）阶段在致癌过程中可能尤为重要。
