Dong Yanfang, Wang Yaxiao, Zhuang Puxiang, Fu Xianzhi, Zheng Yi, Sanche Léon
State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350116, P.R. China.
Department of Nuclear Medicine and Radiobiology and Clinical Research Center, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
J Phys Chem B. 2020 Apr 23;124(16):3315-3325. doi: 10.1021/acs.jpcb.0c00946. Epub 2020 Apr 13.
The molecular mechanism of platinum-based drugs in concomitant chemoradiation therapy relies on enhancement of DNA damage in cancer cells, particularly that of detrimental clustered lesions and cross-links induced by the abundant low-energy electrons (LEEs) generated by ionizing radiation. We provide the complete 1-20 eV electron-energy dependence of the yields of all conformational LEE-induced lesions to biological DNA, when it binds to five molecules of the chemotherapeutic drug cisplatin. Recording at 1 eV intervals clearly show that the enhancement of all lesions is particularly intense at the energies of core-excited transient molecular anions (i.e., TMAs at 5, 6, and 10 eV). New TMAs are observed at 14 and 18 eV, only in yield functions of cisplatin-DNA complexes. Enhancements of all lesions by cisplatin are quantified over the 1-20 eV range, where maxima appear at 14 and 18 eV. The most detrimental lesions to cell survival exhibit the highest enhancements by factors of 2-3. Whereas no cluster lesions are induced by electrons of energy <5 eV in DNA, LEEs of any energy cause clustered damages in the complex. These results confirm the current notion that LEEs and TMAs play a dominant role in the molecular mechanism of platinum-drug chemoradiation therapy.
铂类药物在同步放化疗中的分子机制依赖于癌细胞中DNA损伤的增强，特别是由电离辐射产生的大量低能电子（LEE）诱导的有害簇状损伤和交联。当生物DNA与五个化疗药物顺铂分子结合时，我们给出了所有构象的LEE诱导损伤对生物DNA产率的完整1-20 eV电子能量依赖性。以1 eV间隔进行记录清楚地表明，在核心激发瞬态分子阴离子（即5、6和10 eV处的TMA）的能量下，所有损伤的增强尤为强烈。仅在顺铂-DNA复合物的产率函数中，在14和18 eV处观察到新的TMA。在1-20 eV范围内对顺铂引起的所有损伤增强进行了量化，其中最大值出现在14和18 eV处。对细胞存活最有害的损伤表现出最高的增强，增强因子为2-3。虽然能量<5 eV的电子在DNA中不会诱导簇状损伤，但任何能量的LEE都会在复合物中引起簇状损伤。这些结果证实了当前的观点，即LEE和TMA在铂类药物放化疗的分子机制中起主导作用。
