Upp J R, Beauchamp R D, Townsend C M, Barranco S C, Singh P, Rajaraman S, James E, Thompson J C
Department of Surgery, University of Texas Medical Branch, Galveston 77550.
Cancer Res. 1988 Jun 1;48(11):3265-9.
We studied the effect of inhibition of polyamine biosynthesis by alpha-difluoromethylornithine on the growth of a human gastric adenocarcinoma (CLEES) xenotransplanted in nude mice. CLEES is a well-differentiated gastric adenocarcinoma of the intestinal type. The doubling time has ranged from 7 to 10 days through 11 passages. Electron microscopic and immunohistochemical studies comparing the original tumor and xenotransplants showed similar structure and similar amounts of carcinoembryonic antigen. Polyamine biosynthesis is required for cell division. alpha-Difluoromethylornithine inhibits ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. In this study, 48 athymic mice were used in two experiments. In the first experiment, two groups of 12 mice each were inoculated with CLEES tumor cells and received either tap water or a 3% alpha-difluoromethylornithine solution as drinking water. Tumor size was measured twice weekly. Tumor size was significantly decreased from controls by the fourth week of treatment and at all points of analysis thereafter for 7 wk. In the second experiment, alpha-difluoromethylornithine significantly reduced tumor concentrations of the polyamines putrescine and spermidine. In addition, the tumor content of DNA was significantly reduced in treated mice (0.64 +/- 0.16 mg) compared to controls (4.76 +/- 0.92 mg). Our data suggest that inhibition of polyamine biosynthesis may be a useful component of multidrug chemotherapy for human gastric adenocarcinoma. Establishment of tumor lines such as this gastric adenocarcinoma will facilitate further studies on the biological behavior of human gastric cancer and its response to chemotherapeutic manipulation in vivo.
我们研究了α-二氟甲基鸟氨酸抑制多胺生物合成对裸鼠体内异种移植的人胃腺癌（CLEES）生长的影响。CLEES是一种高分化的肠型胃腺癌。经过11代传代培养，其倍增时间为7至10天。对原发肿瘤和异种移植瘤进行的电子显微镜和免疫组织化学研究显示，它们具有相似的结构和相似数量的癌胚抗原。细胞分裂需要多胺生物合成。α-二氟甲基鸟氨酸抑制鸟氨酸脱羧酶，这是多胺生物合成中的限速酶。在本研究中，48只无胸腺小鼠用于两项实验。在第一个实验中，两组各12只小鼠接种CLEES肿瘤细胞，并分别饮用自来水或3%的α-二氟甲基鸟氨酸溶液。每周两次测量肿瘤大小。到治疗第四周时，肿瘤大小与对照组相比显著减小，此后在所有分析点上持续7周均如此。在第二个实验中，α-二氟甲基鸟氨酸显著降低了肿瘤中多胺腐胺和亚精胺的浓度。此外，与对照组（4.76±0.92毫克）相比，经治疗小鼠的肿瘤DNA含量显著降低（0.64±0.16毫克）。我们的数据表明，抑制多胺生物合成可能是人类胃腺癌多药化疗的一个有用组成部分。建立这样的胃腺癌肿瘤系将有助于进一步研究人类胃癌的生物学行为及其在体内对化疗操作的反应。
