MTH1抑制剂在癌症治疗中的研究进展

The Research Progress of MTH1 Inhibitors in Cancer Treatment

MTH1 (MutT homolog 1)作为一种焦磷酸酶,能够高效清理核苷酸池中的氧化核苷酸,从而保护快速增殖的癌细胞免受高水平ROS带来的致命损伤,但是正常细胞在缺乏MTH1酶时依旧能够通过其他替补途径修复DNA氧化损伤得以存活。在正常细胞及癌细胞中MTH1必要性的显著差异使得靶向MTH1治疗癌症这一疗法成为可能,临床前研究表明,MTH1活性被抑制后或者当MTH1缺乏时能够抑制多种癌症细胞的增殖,且未观察到明显的毒副作用,完美地弥补了传统癌症疗法的种种不足,为癌症疾病的彻底根治带来希望。本文将围绕癌症治疗的瓶颈、ROS与癌症及MTH1的关系、MTH1与癌症相关的功能作用、MTH1抑制剂的发展几点进行综述,旨在阐明癌症治疗手段的新发展,为新药开发奠定理论基础。

MTH1 (MutT homolog 1) can effectively sanitize oxidized nucleotides in the nucleotides pool to pro-tect cancer cells from fatal damage caused by high levels of ROS (reactive oxygen species). In con-trast, the normal cells can repair DNA oxidative damage to survive by the alternative pathway when MTH1 is inhibited. The different importance of MTH1 between normal and cancer cells makes it possible to target MTH1 in treating cancer. Preclinical studies have shown that the inhibition of MTH1 activity or the lack of MTH1 has obvious anti-tumor effect but without side effects, which can perfectly make up for the shortcomings of traditional cancer treatments. To illustrate the new de-velopment of cancer treatments and lay the foundation for new drug development, we will summa-rize the major obstacle to the successful treatment of cancer and the relationship between ROS and cancer and MTH1, illuminate the functional role for MTH1 in tumor biology, and explore the devel-opment of MTH1 inhibitors.