Cisplatin is a chemotherapy drug used to treat numerous cancers, including:
- Bladder
- Head and neck
- Lung
- Ovaries
- Testicles
Its discovery in the 1960s stemmed from an observation that platinum electrodes inhibited bacterial cell division. This led to the development of the platinum-containing compound, which is now an important medication in oncology.
The Chemical Composition of Cisplatin
Cisplatin is a coordination complex centered around a platinum (Pt) atom, which forms the core of the molecule. The arrangement of atoms bonded to the platinum center gives the molecule a three-dimensional structure known as square planar geometry. In this configuration, the platinum atom lies at the center of a flat square, with the other components at the four corners.
Attached to the central platinum atom are four groups called ligands: two ammonia (NH3) groups and two chloride (Cl) atoms. In the “cis” configuration, the two ammonia groups are positioned on the same side of the platinum atom, adjacent to each other at 90-degree angles. The two chloride atoms are also on the same side.
This spatial arrangement determines the molecule’s biological activity. An alternative form, transplatin, contains the same atoms but has a different geometry where similar ligands are on opposite sides of the platinum atom at 180-degree angles. This structural difference renders transplatin pharmacologically inactive.
How the Structure Interacts with DNA
Once cisplatin enters a cell, the environment facilitates a chemical change. The concentration of chloride inside a cell is lower than in the fluid outside, causing the two chloride ligands on the cisplatin molecule to be replaced by water molecules in a process called aquation. This reaction activates the compound, transforming it into a positively charged and highly reactive form.
The activated platinum complex targets elements within the cell, with its primary target being DNA. It forms a strong, covalent bond with nitrogen atoms on the purine bases of DNA, most commonly guanine. The molecule’s “cis” structure is what allows it to bind effectively.
The adjacent reactive sites on the cisplatin molecule allow it to bind to two adjacent guanine bases on the same strand of DNA, creating a 1,2-intrastrand crosslink. This binding event physically distorts the DNA double helix, pulling the bases closer together and inducing a bend in the DNA strand. This structural alteration is the primary damage caused by the drug.
Cellular Consequences of DNA Binding
The kink cisplatin forms in the DNA helix is difficult for the cell’s repair systems to mend. When a cell prepares to divide, it must first replicate its genome. The replication machinery moves along the DNA strand to read the genetic code and synthesize a new copy.
When this machinery encounters the cisplatin-induced bend, the process stalls. The platinum adduct acts as a roadblock, preventing replication enzymes from proceeding. This halt in DNA synthesis signals damage, which the cell’s internal monitoring systems detect.
This detection triggers a process of programmed cell death, known as apoptosis, where the cell initiates a self-destruct sequence. Since cancer cells are characterized by rapid and uncontrolled division, they attempt to replicate their DNA more frequently than most normal cells. This makes them more susceptible to the replication-halting effects of cisplatin, leading to their destruction.
Structural Analogs and Clinical Significance
The success of cisplatin spurred the development of other platinum-based drugs. Scientists modified the original structure to create analogs like carboplatin and oxaliplatin. These compounds retain the central platinum atom and square planar geometry but feature different ligand groups.
In carboplatin, a cyclobutanedicarboxylate ligand replaces the two chloride ligands of cisplatin. This structural change makes carboplatin less reactive than cisplatin. The clinical benefit is a reduction in side effects, particularly kidney damage (nephrotoxicity) and nerve damage (neurotoxicity), which are limitations of cisplatin therapy.
Oxaliplatin features a diaminocyclohexane ligand in place of the ammonia groups. This change allows oxaliplatin to be effective against certain cancers that have developed resistance to cisplatin. The bulkier ligand structure helps the drug form different DNA adducts that are more difficult for a cancer cell’s repair mechanisms to overcome.