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DNA radiosensitization by terpyridine-platinum: damage induced by 5 and 10 eV transient anions

Chemoradiation therapy (CRT), which combines a chemotherapeutic drug with ionizing radiation (IR), is the most common cancer treatment. At the molecular level, the binding of Pt-drugs to DNA sensitizes cancer cells to IR, mostly by increasing the damage induced by secondary low-energy (0-20 eV) electrons (LEEs). We investigate such enhancements by binding terpyridine-platinum (Tpy-Pt) to supercoiled plasmid DNA. Fifteen nanometer thick films of Tpy-Pt-DNA complexes in a molar ratio of 5 : 1 were irradiated with monoenergetic electrons of 5 and 10 eV, which principally attach to the DNA bases to form transient anions (TAs) decaying into a multitude of bond-breaking channels. At both energies, the effective yields of crosslinks (CLs), base damage (BD) related CLs, single and double strand breaks (SSBs and DSBs), non-DSB-cluster lesions, loss of supercoiled configuration and base lesions are 6.5 ± 1.5, 8.8± 3.0, 88 ± 11, 5.3 ± 1.3, 9.6 ± 2.2, 106 ± 17, 189 ± 31 × 10-15 per electron per molecule, and 11.9 ± 2.6, 19.9 ± 4.4, 128 ± 18, 7.7 ± 3.0, 13.4 ± 3.9, 144 ± 19, 229 ± 42 × 10-15 per electron per molecule, respectively. DNA damage increased 1.2-4.2-fold due to Tpy-Pt, the highest being for BD-related CLs. These enhancements are slightly higher than those obtained by the conventional Pt-drugs cisplatin, carboplatin and oxaliplatin, apart from BD-related CLs, which are about 3 times higher. Enhancements are related to the strong perturbation of the DNA helix by Tpy-Pt, its high dipole moment and its favorable binding to guanine (G), all of which increase bond-breaking via TA formation. In CRT, Tpy-Pt could considerably enhance crosslinking within genomic DNA and between DNA and other components of the nucleus, causing roadblocks to replication and transcription, particularly within telomeres, where it binds preferentially within G-quadruplexes.

 

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Tpy-Pt, a terpyridine-platinum drug, is shown to increase DNA damage in cancer cells compared to conventional Pt-drugs, such as cisplatin, carboplatin and oxaliplatin, when used in chemoradiation therapy (CRT) through its binding to DNA and increasing the damage induced by low-energy electrons.

Related Products

Cat.No. Product Name Information
S1215 Carboplatin Carboplatin, a derivative of CDDP, is a DNA synthesis inhibitor which binds to DNA, inhibits replication and transcription and induces cell death and interfers with the cell's repair mechanism in A2780, SKOV-3, IGROV-1, and HX62 cells. It induces the formation of DNA interstrand crosslinks and DNA-protein crosslinks. Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.

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