Cisplatin is a common chemotherapy drug in the treatment of various cancers, including testicular, ovarian, bladder, and lung cancers. Its effectiveness stems from its ability to interfere with cellular processes, leading to cancer cell death. Understanding how this compound operates is important for comprehending its role in modern cancer therapy.
What is Cisplatin?
Cisplatin, also known as cis-diamminedichloroplatinum(II), is a platinum-based compound. It features a central platinum atom bonded to two ammonia (amine) ligands and two chloride ligands, arranged in a specific “cis” configuration. This specific “cis” arrangement is important for its therapeutic properties, as its “trans” isomer is ineffective against cancer cells.
Cisplatin’s Interaction with DNA
Once administered, cisplatin enters cancer cells. Inside the cell, particularly within the nucleus, cisplatin undergoes a transformation where its chloride ions are replaced by water molecules, forming a reactive, positively charged complex. This activated form binds to the cancer cell’s DNA. The primary binding targets within the DNA are the nitrogen atoms at the N7 position of purine bases, especially guanine bases, though it can also interact with adenine bases.
This binding leads to the formation of “DNA adducts,” which are distortions in the DNA structure. The most common types are intrastrand cross-links, where cisplatin binds to two bases on the same DNA strand. Approximately 90% of these intrastrand adducts are 1,2-intrastrand d(GpG) adducts, involving two adjacent guanine bases. Another 10% are typically 1,2-intrastrand d(ApG) adducts, linking an adenine and a guanine. Less frequently, 1,3-intrastrand d(GpXpG) adducts can form, where a third base separates the two platinated guanines.
Cisplatin can also form interstrand cross-links, connecting guanine bases on opposite DNA strands, although these are less common, accounting for about 2% of adducts. These cross-links, particularly the intrastrand adducts, cause significant structural changes to the DNA double helix. The DNA becomes kinked, bent, and unwound, which distorts its normal conformation. These distortions prevent the enzymes responsible for DNA replication (DNA polymerase) and transcription (RNA polymerase) from moving effectively along the DNA strand, thus hindering these essential cellular processes.
How DNA Damage Leads to Cell Death
The DNA damage inflicted by cisplatin triggers a cascade of cellular responses. Cells possess DNA damage response pathways designed to detect and repair lesions. Proteins like p53 are recruited to the sites of DNA damage. The cell attempts to repair the damaged DNA, often utilizing pathways such as nucleotide excision repair.
If the DNA damage is extensive or cannot be repaired, these repair mechanisms become overwhelmed. Persistent damage and the inability to replicate or transcribe DNA lead to cell cycle arrest, halting cell division. When repair is not feasible, the cell initiates programmed cell death, a process known as apoptosis. Apoptosis is a controlled process where the cell systematically dismantles itself, preventing uncontrolled proliferation. This ensures that cells with irreparably damaged DNA are eliminated, which is the goal of cisplatin therapy.
Why Cisplatin Targets Cancer Cells
Cisplatin targets cancer cells due to their rapid division. Cancer cells have a higher rate of DNA replication than healthy cells. This heightened activity makes their DNA more accessible and more susceptible to the drug’s damaging effects.
Cisplatin also targets rapidly dividing healthy cells, like those in bone marrow, the gastrointestinal tract, and hair follicles, but its impact is more pronounced on cancer cells. Cancer cells may also have less efficient DNA repair or altered apoptotic pathways, making them less capable of recovering from cisplatin-induced DNA damage. This differential susceptibility contributes to cisplatin’s effectiveness in cancer treatment.