Platinum (Pt)-containing drugs, or platinating agents such as cisplatin, carboplatin and oxaliplatin are chemotherapy agents used in the treatment of several cancer types such as head and neck, testicular, ovarian, cervical, colorectal and non-small cell lung tumors. It is agreed that the main target of these compounds is DNA with the drugs forming DNA adducts. Pt-induced DNA lesions activate the DNA damage response machinery halting DNA replication and promoting cell cycle arrest, nucleotide ex
cision repair (NER) pathway and apoptosis and as such, they are toxic to proliferating cells like cancer cell. Both p53-dependent and independent routes of apoptosis activation are reported; necrotic-like cell death can also occur. Some tumors however, develop resistance while others may not respond to treatment. For instance, increased NER activity (repair rather than apoptosis) can lead to decreased sensitivity/increased resistance to drugs. Processes that affect the intracellular concentration of drugs can also contribute to drug sensitivity or resistance. In addition, the response can be toxic to non-cancer cells. The relative efficacy and/or toxicity as well as the molecular details of DNA lesions exhibited by the three drugs are different. Cisplatin appears to have the lead in terms of both potency and the toxicity of its side effects. Peripheral neurotoxicity, nephrotoxicity and ototoxicity are among the most severe cisplatin reported side effects. The pharmacokinetics/pharmacodynamics of cisplatin are presented in this diagram; the toxic responses in a related diagram. The pharmacokinetics of cisplatin are primarily exemplified by the influx and efflux of the drug. Passive transport is a route for cisplatin circulation; however, a number of transporters are involved in the uptake, intracellular trafficking and release of cisplatin. A main influx transporter is the high affinity copper transporter of the solute family 31 - Slc31a1, known as Ctr1. Knockout of Ctr1 in a mouse model, abolishes the cisplatin tumor response. Efflux of cisplatin is mediated by two P-type copper transporting ATPases, Atp7a and 7b. The enzymes are localized to the trans-Golgi and are involved in the sequestration and efflux of copper and cisplatin towards the plasma membrane. Copper is delivered to the enzymes by the copper chaperone Atox1; cisplatin can bind both the Cu-free and the Cu-loaded Atox1. By sequestering cisplatin in the cytoplasm, Atox1 is a candidate for drug resistance, as are the ATPases. Interestingly, cisplatin also promotes unfolding of Atox1. Once inside the cells, cisplatin becomes aquated by the gain of two molecules of water and as such is capable of interacting with nucleophilic molecules such as RNA, proteins, phospholipids and DNA , which is its primary target. Inside nucleus, cisplatin interacts with DNA bases where it favors the N7 of purines, primarily forming 1,2-intrastrand adducts between adjacent guanosines (click to access the PDB entry for the crystal structure). and to a lesser extent, 1,3-intrastrand ( click to access the PDB entry for the solution structure), interstrand (click to access the PDB entry for the crystal structure) and mono Pt-DNA adducts. Intrastrand crosslinks bend the DNA double helix toward the major groove and also unwind the DNA; the magnitude of unwinding depends on the identity of the base. Interstrand lesions bend the DNA toward the minor groove, promote extrusion of cytosines at the crosslinked sites and severely unwind the DNA. Cisplatin-DNA adducts are bound with high specificity by a number of proteins, including transcription factors, resulting in inhibition of transcription which may further contributing to the cytotoxicity of the drug and its efficacy in chemotherapy. Proposed mechanisms for the inhibition of transcription include: hijacking of transcription factors (the adduct promotes a bent DNA structure akin to its protein-bound form); blocking of polymerases and precluding elongation; inhibition of chromatin remodeling. Platinated nucleosomes may exhibit a lower level of mobility (click to access the PDB entry for the crystal structure of a cisplatinated nucleosome). The mechanisms of cisplatin nuclear transport are not well understood. Many details of cisplatin actions and associated effects are still to be delineated. To see the ontology report for annotations, Gviewer and download, click here...(less)