Russell K J, Wiens L W, Demers G W, Galloway D A, Le T, Rice G C, Bianco J A, Singer J W, Groudine M
Department of Radiation Oncology, University of Washington Medical Center, Seattle 98195-6043, USA.
Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5):1099-106. doi: 10.1016/s0360-3016(96)00432-4.
To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53.
A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation.
Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans.
This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.
开发一种基于检查点的策略，用于对p53功能缺陷和/或突变的人类肿瘤进行优先放射增敏。
通过用来自16型人乳头瘤病毒的E6癌基因转导，产生了p53肿瘤抑制基因表达不同的A549人肺腺癌细胞系。表达E6的细胞（E6+）在受到电离辐射后缺乏G1期阻滞，p53和p21表达缺陷，并且在接受10 Gy辐射后克隆形成存活率高五倍。
与转导LXSN+载体的对照相比，用毫摩尔浓度的甲基黄嘌呤己酮可可碱（PTX）进行辐照后孵育，可使E6+细胞优先放射增敏。LXSN+细胞有三倍的增敏效果，E6+细胞有15倍的增敏效果，这使得两种细胞系的克隆形成存活率相等。流式细胞术显示PTX消除了两种细胞系的辐射诱导的G2期阻滞。PTX还延长了两种细胞系的G1期进程。使用新型甲基黄嘌呤利索茶碱（LSF）的初步结果表明，其对G1和G2期有类似的细胞周期作用，并且在人可耐受的微摩尔浓度下实现了差异放射增敏。
这种基于检查点的策略是一种有前景的方法，可实现相对于p53+正常组织对p53缺陷肿瘤的优先放射增敏。
