This Medical Video: 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 Cisplatins 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.