Cisplatin is a chemotherapy medication used to treat a number of cancers. This includes testicular cancer, ovarian cancer, breast cancer, bladder cancer, head and neck cancer, cervical cancer, lung cancer, mesothelioma, esophageal cancer, brain tumors, and neuroblastoma. It is used by injection into a vein. Cisplatin is administered intravenously as a short-term infusion in normal saline for treatment of solid malignancies. Cisplatin interferes with DNA replication, which kills the fastest proliferating cells, which in theory are carcinogenic. Following administration, one of the two chloride ligands is slowly displaced by water to give the aquo complex cis-[PtCl(NH3)2(H2O)]+, in a process termed equation. Dissociation of the chloride ligand is favored inside the cell because the intracellular chloride concentration is only 3–20% of the approximately 100 mM chloride concentration in the extracellular fluid. The aqua ligand in cis-[PtCl(NH3)2(H2O)]+ is itself easily displaced by the N-heterocyclic bases on DNA. Guanine preferentially binds. Subsequent to the formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. In 2008, researchers were able to show that the apoptosis induced by cisplatin in human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial platinum responsiveness is high but the majority of cancer patients will eventually relapse with the cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosis and increased DNA repair.