<unk>  interferes with DNA replication, which kills the fastest proliferating cells, which in theory are cancerous. Following administration, one chloride ion is slowly displaced by water to give the aquo complex<unk> Cl(NH3)2(H2O)+, in a process termed aquation. Dissociation of the chloride 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 water molecule in<unk> Cl(NH3)2(H2O)+ is itself easily displaced by the N-heterocyclic bases on DNA. Guanine preferentially binds. Subsequent to formation of PtCl(guanine-DNA)(NH3)2+, crosslinking can occur via displacement of the other chloride, typically by another guanine.<unk>  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<unk>  on human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. Since this was only demonstrated for colon carcinoma cells, it remains an open question whether the Omi/Htra2 protein participates in the<unk> -induced apoptosis in carcinomas from other tissues. Most notable among the changes in DNA are the 1,2-intrastrand cross-links with purine bases. These include 1,2-intrastrand d(GpG) adducts, which form nearly 90% of the adducts, and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide excision repair (NER). Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to<unk> 's activity. Interaction with cellular proteins, particularly HMG domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action.<unk>  resistance<unk>  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<unk> -resistant disease. Many mechanisms of<unk>  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. Oxaliplatin is active in highly<unk> -resistant cancer cells in the laboratory; however, there is little evidence for its activity in the clinical treatment of patients with<unk> -resistant cancer. The drug paclitaxel may be useful in the treatment of<unk> -resistant cancer; the mechanism for this activity is unknown. Transplatin Transplatin, the trans-stereoisomer of<unk> , has formula trans-trans-PtCl2(NH3)2 and does not exhibit a comparably useful pharmacological effect. Two mechanisms have been suggested to explain the reduced anticancer effect of transplatin. Firstly, the trans arrangement of the chloro ligands is thought to confer transplatin with greater chemical reactivity, causing transplatin to become deactivated before it reaches the DNA, where<unk>  exerts its pharmacological action. Secondly, the stereo-conformation of transplatin is such that it is unable to form the characteristic 1,2-intrastrand d(GpG) adducts formed by<unk>  in abundance.
Cisplatin
Ifosfamide
Bleomycin
Carboplatin
Vincristine
Mitoxantrone
Etoposide
Daunorubicin