The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity.
The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity.
复制标题
DOI：
10.3892/ijo.15.2.209
复制
发表时间：
1999-08
影响因子：
5.2
通讯作者：
N. Prabhu;K. Somasundaram;H. Tian;G. Enders;K. Satyamoorthy;M. Herlyn;W. El-Deiry
中科院分区：
文献类型：
--
作者：
N. Prabhu;K. Somasundaram;H. Tian;G. Enders;K. Satyamoorthy;M. Herlyn;W. El-Deiry
细胞周期蛋白依赖性激酶抑制剂是细胞生长的有效抑制剂，并已被提议作为癌症基因替代治疗的靶点。p16 INK 4a或p21 WAF 1的表达保护细胞免受拓扑异构酶II抑制剂依托泊苷的细胞毒性作用。在表达CDK受体的依托泊苷暴露细胞中诱导较低水平的p53，这表明保护可能是由于生长停滞细胞中较低水平的DNA损伤。暴露于p16 INK 4a或p21 WAF 1的人骨肉瘤细胞在依托泊苷治疗之前和治疗期间保护细胞免受依托泊苷诱导的细胞死亡。在暴露于依托泊苷后，Ad-p16 INK 4a或Ad-p21 WAF 1感染细胞导致保护作用丧失，并有证据表明生长抑制增强。结果表明，DNA损伤依托泊苷化疗和细胞周期抑制治疗的管理时间表是产生的细胞毒性的主要决定因素。
Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.