The Mechanism of Cisplatin (New -HD)

Cisplatin is in a class of drugs known as platinum-containing compounds used to treat various types of cancers including metastatic testicular and ovarian tumors. The molecule was first discovered in 1845, but did not receive FDA approval until 1978. Today it is known as the "penicillin of cancer drugs," because it is so effective for many different cancers. There are three key players involved in Cisplatin's mechanism: (1) Cisplatin, (2) DNA (3) and an HMG Protein. Most Cisplatin enters the body through active transport, but some molecules are passively defused through the cell membrane. Once in the nucleus, Cisplatin can form an adduct with two consecutive guanine bases within a strand of DNA. The molecule loses its chlorine atoms in exchange for the nitrogen atoms of the target guanines. Cisplatin can bond more tightly with nitrogen because nitrogen balances the platinum charge more effectively than chlorine. It is this adduct-induced DNA bend that allows binding of proteins which contain the high mobility group, HMG domain. Once the protein is bound to the DNA, it inserts a wedge-like phenyl group of phenylalanine 37 into the widened minor groove created by the bend. The tightly bound HMG protein causes destacking of the nucleotide bases, resulting in the DNA helix becoming kinked. In this way, Cisplatin can be thought of as a monkey wrench in the DNA repair system. With the HMG protein bound to the DNA, the modified strand is not repaired properly and so the cell dies. The success of Cisplatin depends on its ratio of efficacy between cancerous and healthy cells.

Created by Nicholas O'Brien (Technical Consultant); Bongsup Cho (Professor of Pharmacy).