MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.
MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.
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DOI：
10.1158/1078-0432.ccr-11-0650
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Meyn RE
中科院分区：
文献类型：
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作者：
Bridges KA;Hirai H;Buser CA;Brooks C;Liu H;Buchholz TA;Molkentine JM;Mason KA;Meyn RE
放射治疗通常用于治疗多种实体瘤。然而，在一些疾病部位的治疗比率的改善是迫切需要的，这导致我们评估分子靶向治疗作为放射增敏剂。本研究的目的是评估wee1激酶抑制剂MK-1775对人类肿瘤细胞放射致敏的能力。通过克隆生存试验，对来自肺癌、乳腺癌和前列腺癌的人肿瘤细胞进行MK-1775放射致敏试验。包括p53野生型和p53缺陷系。通过流式细胞术和检测γ-H2AX病灶，确定了MK-1775消除辐射诱导的G2阻滞，从而使含有DNA损伤的细胞过早进入有丝分裂的能力。以人肺癌细胞系作为异种移植瘤在裸鼠体内生长，通过肿瘤生长延迟实验评估MK-1775与辐射联合的体内疗效。克隆生存分析表明，纳米摩尔浓度的MK-1775可致敏p53缺陷的人肺癌、乳腺癌和前列腺癌细胞，但与野生型p53不相似。与其放射致敏能力一致，MK-1775在p53缺陷细胞中消除了辐射诱导的G2阻滞，但在p53野生型细胞系中没有。在肿瘤生长延迟研究中，MK-1775也显著增强了体内辐射的抗肿瘤效果，同样是针对p53缺陷的肿瘤。这些结果表明，在体外和体内，p53缺陷的人肿瘤细胞被强效和选择性的wee1激酶抑制剂MK-1775显著地放射增敏。综上所述，我们的研究结果有力地支持了MK-1775联合放疗的临床评价。
Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G2 block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice. Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G2 block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the anti-tumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors. These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.