Mechanism of Action

Cisplatin is believed to kill cancer cells by binding to DNA and interfering with its repair mechanism, eventually leading to cell death.
The first step in the process (after the cisplatin molecule penetrates the cell membrane intact) is for a molecule of water to replace one of the chloride ions. The resulting structure can then bind to a single nitrogen on a DNA nucleotide. Then, the second chloride is replaced by another H2O and the platinum binds to a second nucleotide. Binding studies of cisplatin with DNA have indicated a preference for nitrogen 7 on two adjacent guanines on the same strand. It also binds to adenine and across strands to a lesser extent.
The cisplatin-DNA complex attracts the attention of HMG (high mobility group)-1 and other DNA repair proteins which become irreversibly bound. The resulting distortion to the shape of the DNA prevents effective repair. (The trans isomer of cisplatin is unable to form 1,2 intrastrand links and lacks antineoplastic activity.)
Other antineoplastic agents, such as etoposide, contribute to the platinum-DNA-protein complex and thus synergistically reinforce the activity of cisplatin.

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Normal DNA

(19-mer DNA unit extracted from PDB entry 1D66, courtesy of Eric Martz)

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Cisplatin bound to DNA

(from PDB Entry 1AU5)

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Cisplatin bound to DNA

(from PDB Entry 1A84)

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Cisplatin bound to DNA, along with High Mobility Group 1 Protein

(from PDB Entry 1CKT)

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