Cisplatin is a chemotherapy agent used to treat many cancers, including those of the bladder, lung, and ovaries. Its effectiveness comes from its ability to damage the DNA within rapidly dividing cells. This action is especially harmful to cancer cells, which are defined by their high rate of proliferation, and ultimately leads to their death.
Mechanism of Cisplatin Action
Cisplatin is administered intravenously and remains stable in the bloodstream’s high-chloride environment. Upon entering a cell, the lower internal chloride concentration causes a chemical reaction. The cisplatin molecule loses its chloride atoms, which are replaced by water molecules in a process called aquation. This transforms cisplatin into a highly reactive, positively charged state.
This activated form of cisplatin is drawn to the negatively charged DNA in the cell’s nucleus. It has a strong preference for binding to guanine bases, though it can also bind to adenine. Its interaction with guanine is the most common and significant for its anti-cancer effects.
Once bound, cisplatin forms strong links, known as adducts, with the DNA. The most frequent type of damage is a 1,2-intrastrand crosslink, where the drug connects two adjacent guanine bases on the same strand of the DNA helix. A less common but more disruptive form is the interstrand crosslink, which connects bases on opposite strands of the DNA, effectively stapling the two strands together.
Consequences for Cancer Cells
The formation of cisplatin-DNA adducts causes significant distortion of the DNA double helix. These crosslinks create bends and kinks that act as roadblocks for cellular machinery. This structural alteration prevents enzymes from moving along the DNA strand, so the cell can no longer copy its DNA for division (replication) or read its genetic code to produce proteins (transcription).
Sensing this damage, the cell activates cell cycle checkpoints. These checkpoints halt cell division, a state known as cell cycle arrest. This pause gives the cell an opportunity to repair the DNA damage, a protective measure to prevent creating new cells with a corrupted genome.
If the DNA damage is too severe for the cell’s repair systems to manage, the checkpoints initiate a self-destruct process called apoptosis. This programmed cell death eliminates the compromised cancer cell. Forcing the cancer cell to undergo apoptosis is the intended therapeutic outcome of cisplatin treatment.
Cellular Repair and Drug Resistance
Cells possess molecular systems designed to find and fix DNA damage. The primary pathway for repairing the adducts created by cisplatin is the Nucleotide Excision Repair (NER) system. This system recognizes the distortion in the DNA helix, cuts out the damaged segment, and synthesizes a new, correct piece of DNA to replace it.
The effectiveness of the NER pathway determines if a cancer cell survives treatment. Some tumor cells may have a more efficient NER system, allowing them to repair the damage and survive. These surviving cells can then proliferate, leading to a new tumor population that is resistant to the drug.
Cancer cells can also develop resistance through other mechanisms. Some reduce the amount of cisplatin that enters by altering transport proteins on the cell surface. Others increase the activity of molecular pumps that eject the drug before it reaches the DNA.
Effects on Non-Cancerous Tissues
Cisplatin’s mechanism is not specific to cancer cells; it affects any rapidly dividing cell. This lack of selectivity is the reason for many side effects, as it also damages healthy, high-turnover tissues. This includes cells in the bone marrow, hair follicles, and the gastrointestinal tract, leading to low blood counts, hair loss, and nausea.
Certain organs are particularly susceptible to damage due to their role in processing the drug. The kidneys are a primary site of toxicity, a condition known as nephrotoxicity. As the kidneys filter blood, they concentrate cisplatin, leading to high-level exposure that damages kidney cells. This is a significant and often dose-limiting side effect.
The drug can also cause damage to the nervous system and auditory system. Neurotoxicity occurs when cisplatin harms nerve cells, resulting in symptoms like tingling or numbness in the hands and feet. Ototoxicity, or hearing loss, happens when the drug damages the delicate cells within the inner ear.