MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines.
MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines.
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DOI：
10.1186/1471-2407-11-211
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发表时间：
2011-05-30
期刊：
影响因子：
3.8
通讯作者：
Myklebost O
中科院分区：
文献类型：
--
作者：
Ohnstad HO;Paulsen EB;Noordhuis P;Berg M;Lothe RA;Vassilev LT;Myklebost O
当前肉瘤治疗的频繁失败和严重副作用需要新的治疗方法。小分子 MDM2 拮抗剂 Nutlin-3a 激活 p53 通路，并有效诱导 MDM2 基因扩增和 MDM2 蛋白过表达的肿瘤细胞凋亡。然而，大多数人类肉瘤具有正常水平的 MDM2，并且 MDM2 拮抗剂在该组中的治疗潜力仍不清楚。我们研究了 Nutlin-3a 是否可用于增强对传统疗法的反应和/或减少化疗的基因毒性负担。用 Nutlin-3a 联合阿霉素、甲氨蝶呤或顺铂处理一组具有不同 TP53 和 MDM2 状态的肉瘤细胞系，并测定它们的联合指数。当阿霉素和 Nutlin-3a 在具有野生型 TP53 和扩增的 MDM2 的细胞系中组合，或者在 MDM2 正常和扩增的肉瘤细胞系中与甲氨蝶呤组合时，观察到明显的协同作用，从而使细胞毒性药物剂量减少多达十倍。有趣的是，Nutlin-3a 似乎在 TP53 突变的细胞系中增强了阿霉素和顺铂等经典药物的作用，但抑制了甲氨蝶呤的作用。 Nutlin 与经典肉瘤化疗联合使用显示出有希望的临床前潜力，但由于仍缺乏明确的生物标志物，因此临床试验应进行详细的肿瘤分析。
Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified MDM2 gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy. A panel of sarcoma cell lines with different TP53 and MDM2 status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined. Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate. The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.
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影响因子：
37.3
作者：
Berg M;Agesen TH;Thiis-Evensen E;INFAC-study group;Merok MA;Teixeira MR;Vatn MH;Nesbakken A;Skotheim RI;Lothe RA
通讯作者：
Lothe RA
影响因子：
4.8
作者：
Hu, Baoli;Gilkes, Daniele M.;Chen, Jiandong
通讯作者：
Chen, Jiandong
影响因子：
4.3
作者：
Korotchkina, Lioubov G.;Demidenko, Zoya N.;Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
DOI：
10.1093/jnci/86.17.1297
发表时间：
1994-09-07
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
FLORENES, VA;MAELANDSMO, GM;FODSTAD, O
通讯作者：
FODSTAD, O
影响因子：
5.7
作者：
Cao, C;Shinohara, ET;Lu, B
通讯作者：
Lu, B