INVESTIGATING CIS PLATIN INTERACTIONS WITH TELOMERE DNA

顺铂（cis-diaminedichloroplatinum，cis-DDP）是金属药物中最广泛的处方药，因为它用于治疗多种类型的癌症。 一些研究表明，顺铂的细胞毒性活性可能与药物对端粒和端粒酶的作用有关。 癌细胞暴露于顺铂导致端粒缩短以及端粒酶活性抑制。 尽管迄今为止的研究，很少有人知道顺铂与端粒DNA重复序列，端粒四链体结构，或端粒酶在体外的相互作用。顺铂与重复端粒DNA序列的相互作用。 该研究将开始，确定顺铂对端粒重复序列的偏好超过随机的富G序列。 这项工作将遵循顺铂与单链端粒重复序列，可以形成G-四链体结构的相互作用的调查。 将使用各种已建立的化学和光谱技术（包括凝胶迁移率测定、HPLC、原子吸收光谱（AAS）、圆二色谱（CD）、核磁共振（195 Pt和1H NMR）和X射线晶体学）对这些相互作用进行分子动力学、动力学和结构表征。 此外，还探讨了DNA铂化对端粒酶活性的影响。 计划中的研究有望阐明端粒损伤和端粒酶抑制在顺铂细胞毒活性中的重要性。

Cisplatin (cis-diaminedichloroplatinum, cis-DDP) is the most widely prescribed at the metallopharmaceutical, as it is used to treat many types of cancer. Several studies have suggested that cytotoxic activity of the cisplatin may be linked to the effect of the drug on telomeres and the telomerase enzyme. Exposure of cancer cells to cisplatin results in both telomere shortening, as well as a suppression of telomerase activity. Despite the studies to date, very little is known about the interaction of cisplatin with telomere DNA repeat sequences, telomere tetraplex structures, or telomerase in vitro. The interaction of cisplatin with repetitive telomere DNA sequences is proposed. The study will begin with determining the preference of cisplatin for telomere repeats over random G-rich sequences. This work will be followed by an investigation of the interaction of cisplatin with single-stranded telomere repeats that can form G-quadruplex structures. These interactions will be thermodynamically, kinetically, and structurally characterized using a variety of established chemical and spectroscopic techniques including gel mobility assays, HPLC, atomic absorption spectroscopy (AAS), circular dichroism (CD), nuclear magnetic resonance (195Pt and 1H NMR), and X-ray crystallography. In add addition, the effect of DNA platination on telomerase activity is also proposed. The planned research is expected to elucidate the importance of telomere damage and telomerase inhibition in the cytotoxic activity of cisplatin.