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Selective pharmacologic activation of the p53-dependent pathway as a therapeutic strategy for hematologic malignancies.

机译:p53依赖途径的选择性药理激活作为血液系统恶性肿瘤的治疗策略。

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摘要

Most of the drugs currently used to treat hematologic cancers are genotoxic agents that exert some of their antitumor activity through p53-dependent mechanisms. However, this activity is achieved at the price of collateral genotoxic damage, which may lead to generation of more malignant tumor subclones and secondary neoplasias. Because p53 remains wild-type in the majority of hematologic malignancies nongenotoxic induction of the p53-pathway is an attractive therapeutic strategy for this group of cancers. Following the recent development of selective small-molecule MDM2-antagonists (nutlins), we have demonstrated that nutlin-treatment of primary tumor cells isolated from patients with multiple myeloma induces p53 target genes and efficiently drives these cells into apoptosis. Because the apoptotic function of p53 appears to be preserved in a number of common hematologic neoplasias it should be used to investigate the utility of non-genotoxic p53-induction therapies.
机译:当前用于治疗血液系统癌症的大多数药物是遗传毒性剂,它们通过p53依赖性机制发挥某些抗肿瘤活性。然而,以附带的遗传毒性损害为代价实现了这种活性,这可能导致产生更多的恶性肿瘤亚克隆和继发性瘤形成。由于在大多数血液系统恶性肿瘤中p53仍为野生型,因此,p53途径的非遗传毒性诱导是该类癌症的一种有吸引力的治疗策略。继选择性小分子MDM2拮抗剂(nutlins)的最新发展之后,我们证明了用nutlin处理从患有多发性骨髓瘤的患者中分离的原发性肿瘤细胞可诱导p53目标基因,并有效地驱动这些细胞凋亡。由于p53的凋亡功能似乎在许多常见的血液肿瘤中得以保留,因此应将其用于研究非遗传毒性p53诱导疗法的实用性。

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