In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002).
In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002).
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发表时间：
2000-03
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通讯作者：
Limin Hu;C. Zaloudek;G. Mills;J. Gray;R. Jaffe
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作者：
Limin Hu;C. Zaloudek;G. Mills;J. Gray;R. Jaffe
磷脂酰肌醇3-激酶(PI3-K)诱导有丝分裂、细胞生长和细胞转化。编码P110α亚单位的基因扩增可能是卵巢癌进展过程中的一个重要事件，PI3-K抑制剂可能是这种疾病的治疗药物。我们评价了PI3-K的有效抑制剂LY294002在体内和体外对卵巢癌生长的影响以及对体内腹水形成的影响。无瘤小鼠腹腔注射。卵巢癌细胞系OVCAR-3。接种后7d，分别给予或不给予LY294002(100 mg/kg体重)治疗3周。每周测量两次体重和腹围。实验结束时，处死小鼠，测量腹水量，并切除肿瘤。与对照组相比，LY294002治疗组的平均肿瘤负担减少了约65%。体外培养的OVCAR-3细胞与LY294002(1、5、10微米)共同培养24小时，1、5、10微米LY294002处理的细胞数分别比对照组减少27、56、75%。体内和体外的形态学研究表明，LY294002可引起肿瘤细胞明显的核固缩和胞浆体积缩小，证实为细胞凋亡。因此，LY294002在体内显著抑制卵巢癌的生长和腹水形成，在体外显著抑制卵巢癌细胞的增殖，提示PI3-K抑制剂作为一种潜在的有效治疗卵巢癌的方法具有重要的作用。
Phosphatidylinositol 3-kinase (PI3-K) induces mitogenesis, cell growth, and cell transformation. Amplification of the gene encoding the P110alpha subunit likely is an important event in ovarian cancer progression, and PI3-K inhibitors are possible therapeutic agents for this disease. We evaluated effects of LY294002, a potent inhibitor of PI3-K, on growth of ovarian carcinoma in vivo and in vitro, and on ascites formation in vivo. Athymic mice were inoculated i.p. with the ovarian cancer cell line OVCAR-3. Seven days after inoculation, mice were treated with or without LY294002 (100 mg/kg of body weight) for 3 weeks. Body weight and abdominal circumference were measured twice weekly. At the end of the experiment, mice were sacrificed, ascites volume was measured, and tumors were excised. Mean tumor burden in the LY294002-treated group was reduced by approximately 65% versus controls. Virtually no ascites developed in the treatment group; mean volume of ascites in controls was 3.3 +/- 0.38 ml. OVCAR-3 cells also were cultured in vitro without and with LY294002 (1, 5, and 10 microM) for 24 h. The number of cells in 1, 5, and 10 microM LY294002-treated wells was reduced by 27, 56, and 75%, respectively, versus controls. In vivo and in vitro morphological studies demonstrated that LY294002 induced marked nuclear pyknosis and diminished cytoplasmic volume in the tumor cells, confirmed as apoptosis. Thus, LY294002 significantly inhibits growth and ascites formation of ovarian carcinoma in vivo and markedly inhibits ovarian cancer cell proliferation in vitro, suggesting an important role of PI3-K inhibitors as a potentially useful treatment for women with ovarian carcinoma.