用放射性标记的抑制剂靶向端粒酶。

Targeting telomerase with radiolabeled inhibitors.

作者信息

Waghorn Philip A, Jackson Mark R, Gouverneur Veronique, Vallis Katherine A

机构信息

CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK.

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

出版信息

Eur J Med Chem. 2017 Jan 5;125:117-129. doi: 10.1016/j.ejmech.2016.09.028. Epub 2016 Sep 10.

The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC of 1.58 μM (MST-312 IC: 0.23 μM). Clonogenic assays showed a dose dependant effect of I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435.

端粒酶在约85%的癌症中表达，而在大多数正常细胞中不存在，这使其成为癌症治疗的一个有吸引力的靶点。然而，端粒酶抑制开始与生长停滞之间的延迟期使得仅直接抑制成为一种不足的治疗方法。然而，已证明端粒酶抑制可增强癌细胞的放射敏感性。为了研究在向癌细胞递送靶向放射性核素治疗的同时抑制端粒酶的策略，合成了放射性碘标记的端粒酶抑制剂，并研究了它们对癌细胞存活的影响。端粒酶抑制剂MST-312的碘标记类似物以1.58 μM的IC抑制端粒酶（MST-312的IC：0.23 μM）。克隆形成试验显示，碘标记的MST-312对端粒酶阳性细胞系MDA-MB-435中的细胞存活具有剂量依赖性作用。