cisplatin

cisplatin, widely used platinum-containing anticancer drug. Cisplatin is one of the earliest examples of a successful metal-based anticancer agent. Since its clinical introduction in the 1970s, it has been a cornerstone of cancer treatment, particularly for testicular cancer, ovarian cancer, bladder cancer, and lung cancer. It is also used for cervical, esophageal, and stomach cancers, often as part of combination chemotherapy regimens. Its use has dramatically improved survival rates in some cases, especially for testicular cancer, where cure rates rose sharply following its adoption.

Discovery and development

Cisplatin was first discovered in 1845 by Italian chemist Michele Peyrone, who synthesized the compound while studying platinum complexes. At the time, its biological activity was not known, and it was simply described as a chemical substance, later referred to as Peyrone’s salt (Peyrone’s chloride). The compound remained of primarily academic interest within chemistry until the 1960s, when its anticancer effects were discovered serendipitously. In his studies of bacteria in the early 1960s, American chemist Barnett Rosenberg noticed a resemblance between the patterns formed by iron filings exposed to a magnetic field and the appearance of chromosomes during cell division. To explore this phenomenon, Rosenberg and colleagues at Michigan State University placed bacterial cell cultures inside a chamber equipped with platinum electrodes, which were presumed to be inert. When the electromagnetic field was switched on, however, the researchers observed a halt in division, though the cells continued to increase in length, in some instances becoming 300 times longer than usual. In subsequent experiments Rosenberg discovered that this effect was due to the presence of cisplatin, a product formed by electrochemical oxidation of platinum electrodes immersed in a nutrient medium that contained ammonium chloride as a pH buffer.

Subsequent experiments showed that cisplatin could inhibit the growth of cancer cells both in cell cultures and in animal models. In the early 1970s the drug entered clinical trials, where it demonstrated remarkable effectiveness against certain cancers, particularly testicular and ovarian cancers. These trials established both its therapeutic potential and its side effects, guiding dosage and treatment protocols. The strong clinical results led to the approval of cisplatin for medical use in 1978, after which it became a foundational anticancer drug and spurred the development of related platinum-based treatments.

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Mechanism of action

Cisplatin exerts its effects by interacting directly with DNA. Once inside the cell, it undergoes chemical activation and forms covalent bonds with DNA, creating cross-links between adjacent bases. These cross-links alter the DNA double helix, interfering with essential processes such as DNA replication and transcription (the synthesis of RNA from DNA). Because cancer cells divide rapidly and rely on accurate DNA copying, they are especially sensitive to this damage. In response, they enter cell cycle arrest (a halt in the cell division cycle), which normally provides cells with the necessary time to repair DNA damage. In cancer cells exposed to cisplatin, however, unrepairable DNA damage triggers apoptosis (programmed cell death), limiting tumor growth.

Side effects and resistance

The action of cisplatin, however, is not entirely selective for cancer cells. Healthy cells that divide frequently—such as those in the bone marrow, digestive tract, and hair follicles—can also be affected, leading to side effects such as nausea, vomiting, fatigue, immunosuppression, and hair loss. In addition, cisplatin is associated with kidney damage (nephrotoxicity), hearing loss (ototoxicity), and nerve damage (peripheral neuropathy).

Resistance to cisplatin can develop when cancer cells become more effective at repairing DNA damage or adapt to reduce drug uptake or to increase drug efflux (their ability to actively pump the drug out of the cell). Thus, cisplatin is often used in combination with other anticancer agents to limit the development of drug resistance and enhance treatment effectiveness. In particular, the use of drugs with different mechanisms of action allows for therapeutic attack of cancer cells at multiple points in the cell cycle, making it more difficult for them to survive and adapt. This approach also allows for lower doses of individual drugs, including cisplatin, which can help reduce toxicity while maintaining therapeutic benefit.