Prasad Gautam, Wang Hui, Agrawal Sudhir, Zhang Ruiwen
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294-0019, USA.
Anticancer Res. 2002 Jan-Feb;22(1A):107-16.
Overexpression of the MDM2 oncogene is one of the molecular characteristics of gliomas. In this study we determined the therapeutic effects of an antisense anti-MDM2 oligonucleotide administered alone or in combination with the clinically used chemotherapeutic agents Paclitaxel and Irinotecan. In cultured cells with various p53 status, U87-MG (p53wt/wt), A172 (p53wt/mt) and T98G (p53mt/mt), the antisense oligonucleotide, produced a dose- and sequence-dependent reduction in MDM2 expression and elevation in p53 (in U87-MG and A172 cells) and p21 levels (in all three cell lines), resulting in an increase in apoptosis and cytotoxicity. Synergistic effects on p53 and p21 levels between the oligonucleotide and chemotherapeutic agents were also observed in vitro. In in vivo studies with U87-MG xenografts, the oligonucleotide inhibited tumor growth and improved the therapeutic efficacy of paclitaxel and irinotecan 39- and 63-fold, respectively. In conclusion, inhibiting MDM2 expression could be a novel pharmacological approach to glioblastoma therapy.
MDM2癌基因的过表达是神经胶质瘤的分子特征之一。在本研究中，我们确定了单独施用或与临床使用的化疗药物紫杉醇和伊立替康联合使用的反义抗MDM2寡核苷酸的治疗效果。在具有不同p53状态的培养细胞U87-MG（p53野生型/野生型）、A172（p53野生型/突变型）和T98G（p53突变型/突变型）中，反义寡核苷酸使MDM2表达呈剂量和序列依赖性降低，p53（在U87-MG和A172细胞中）和p21水平（在所有三种细胞系中）升高，导致细胞凋亡和细胞毒性增加。在体外也观察到寡核苷酸与化疗药物之间对p53和p21水平的协同作用。在用U87-MG异种移植进行的体内研究中，该寡核苷酸抑制肿瘤生长，并分别将紫杉醇和伊立替康的治疗效果提高了39倍和63倍。总之，抑制MDM2表达可能是胶质母细胞瘤治疗的一种新的药理学方法。
