Mechanism of cisplatin

Investigations on the working mechanism of cisplatin have been carried out during the last decade by a variety of research groups, involving chemists, biochemists, biologists and medical researchers17. Early studies already made it clear that reaction of platinum compounds with nucleic adds play an important role in the mechanism of action. The present review deals with the status of this field, with special attention to platinum-DNA interactions. 

In vitro experiments with cultured cell lines have provided a wealth of information about the biological mechanism of cisplatin. Although there is some correlation between the sensitivity of these cells and related tumors... 

There are multiple pathways for p53 induction [161], but the specific mechanism for the activation of p53-mediated responses by cisplatin is still obscure. Details about the DNA-damage signal transduction pathway could be important for the mechanism of cisplatin resistance and must be provided by future research. In contrast, quite a lot is known about the downstream effects of p53. Several of these p53 activities have been implicated in the modulation of cellular sensitivity to cisplatin (Fig. 6). 

The identification of the mechanisms of cisplatin translesion synthesis should allow the refinement of strategies aimed at minimizing the adverse effects of this cellular process. 

Mechanism and susceptibility factors The mechanism of cisplatin-induced neurotoxicity has not been fully explained. Cisplatin appears to affect neurons in the dorsal root ganglia. It has also been suggested that it can act as a calcium channel blocker, altering intracellular calcium homeostasis and leading to apoptosis of exposed neurons, such as those of the dorsal root ganglia. Cisplatin-induced sensory neuropathy is predominantly characterized by symptoms such as numbness and tingling, paresthesia of the upper and lower extremities, reduced deep-tendon reflexes, and leg weakness with gait disturbance. The first symptoms are often observed after a cumulative dose of 300-600 mg/m. Risk factors include diabetes mellitus, alcohol consumption, or inherited neuropathies. Advanced age has not been identified as an independent risk factor when there is no co-morbidity (67-70). 

The mechanisms of cisplatin-induced damage to the outer hairy cells of the cochlea may include the formation of highly reactive oxygen radicals and depletion of glutathione (144). The role of amifostine and glutathione... 

The mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (for example mercury), cisplatin can accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (for example bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (146,195-197). 

Ravi R, Somani SM, Rybak LP (1995) Mechanism of cisplatin ototoxicity antioxidant system. Pharmacol Toxicol 76(6) 386-394... 

These results should not be construed to mean that DNA repair is the only mechanism of cisplatin resistance. There is evidence that relative amounts of glutathione are increased in cisplatin-resistant cells.Glutathione presumably uses its thiol moiety to coordinate platinum and diminish the amount that can bind to DNA. Reduced influx or increased efflux of a drug constitutes additional mechanisms by which cells become resistant. Further studies are required to ascertain which of these possibilities is most important for the cisplatin resistance phenomenon. 

Dedon, P. C., R. Qazi, and R. F. Borch. 1986. Potential mechanisms of cisplatin toxicity of diethyldithiocarbamate rescue. Chem. Abstr. CA 705(19) 164609t. 

Although there are a variety of types of crosslinks that can be formed by cisplatin, the intrastrand crosslinks are the most common. Most of these crosslinks can be repaired but at least one type of interstrand CTOsslink may not induce response of cellular repair enzymes. Further, whereas intrastrand crosslinks are important in describing the activity of cisplatin, inducing apoptosis also appears to be a factor in the mechanism of cisplatin s anticancer activity [104,105]. 

The chemotherapeutic cisplatin, cw-diamminedichloridoplatinum ii (CDDP), is widely used for the treatment of many malignancies, including testicular, ovarian, bladder, cervical, head and neck, and small cell and non-small cell limg cancers (1). There is a large amount of literature on the mechanisms of cisplatin-induced cell death, but its mode of action still remains unclear. Cisplatin may initiate the programmed cell death (apoptosis) via its binding to DNA, which may activate p5 3-dependent apoptotic pathways. Cisplatin, however, can also kill cancer cells with mutated p53 (2-4). Cisplatin may kill cells via multiple modes like apoptosis, necrosis, and perturbation of calciiun homeostasis (3-6). Understanding the mechanisms of cisplatin resistance and toxicity is an area of active research in cancer therapy. 

The geometry of a platinated guanine-guanine-cytosine triplet was computed at the Hartree-Fock level [99IC1481 ]. The mechanism of cisplatin antitumor activity... 

Over the last few years, significant advances in the depth of understanding of the conformational features of the polynucleotide—platinum complex interaction have come from both solution (CD, NMR) and solid-state (X-Ray) studies on oligonucleotide fragments, particularly dinucleotide complexes. Excellent summaries of the status of model studies and their relationship to the molecular mechanism of cisplatin can be found in references [82 and 141]. These complement the earlier reviews [83, 84]. The features outlined do in fact confirm some of those expected from model studies, although there has not been an extensive comparison with the trans-isomcr. 

Santin G, Piccolini VM, Bami S et al (2013) Mitochondrial fusion a mechanism of cisplatin-induced resistance in neiu-oblastoma cells Neurotoxicology 34 51-60... 

The fact that the precise mechanism of cisplatin (and other derivatives) remains elusive, has resulted in a large interest to study metal DNA-binding in... 

A disturbing clinical problem is the development of resistance of certain tumors against cisplatin. Some types of cancer are known to be intrinsically insensitive to cisplatin treatment, whereas other cancers only develop resistance during chemotherapy. Therefore, the applicability of cisplatin still is limited to a relatively narrow range of tumors. The mechanism of cisplatin-resistance seems to be multifactorial, and at least three factors have been identified as possible modulators of the observed cellular resistance These factors are now accepted to be ... 

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