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.
