Cisplatin toxicity

Price PM, Safirstein RL, Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am. J. Physiol. Renal Physiol, 2004 286 F378-F384. 

Fukuishi N and Gemba M. Use of cultured renal epithelial cells for the study of cisplatin toxicity. Jpn J Pharmacol 50 247-249, 1989. 

Gordon JA, Gattone VH. Mitochondrial alterations In cisplatin-induced acute renal failure. Am J Physiol 1986 250 F991-8. Brady HR, Kone BC, StronIskI ME, Zeldel ML, Glebisch G, Gullans SR. Mitochondrial Injury an early event In cisplatin-toxicity to renal proximal tubules. Am J Physiol 1990 258 FI 181-7. 

Cytochrome C release may follow the MPT or occur independently. In a recent study of cisplatin toxicity [27] decrease in oxidative phosphorylation was due to the inhibition of mitochondrial FO-Fl-ATPase activity, but the decrease in oxidative phosphorylation was accompanied by hyperpolarization of the mitochondrial membrane rather than a decrease in membrane potential that is usually associated with the MPT [28]. The studies also demonstrate a marked decrease in active Na transport and Na-K-ATPase activity that paralleled the decrease in FO-Fl-ATPase activity and preceded increases in membrane potential in cisplatin treated renal proximal tubular cells. These studies would suggest that cytochrome C release into the cytoplasm and the subsequent formation of the apoptosome (see below) may occur independently of the MPT and that the initiation of cell death by disruption of energy metabolism can directly engage the caspase cascade. 

Additional evidence linking the kidney s vulnerability to cisplatin transport is provided by autoradiographic studies that show intense uptake of radiolabeled cisplatin in the S3 segments of the proximal nephron [13]. Since the S3 segment of the proximal tubule is the principle site of cisplatin-induced cell toxicity and contains most of the platinum, these studies provide further evidence of the unique vulnerability of this cell type to cisplatin toxicity, depending on its propensity to accumulate and interfere with cisplatin metabo-... 

Another approach to reducing cisplatin toxicity is to develop new classes of platinum drugs or different routes of their administration. Carboplatin (Figure... 

Melanocortins appear to protect damaged central neurons from neurotoxins, as demonstrated in a model employing unilateral destruction of the substantia nigra. Accelerated denervation sensitivity and increased dopamine immunoreactivity in the substantia nigra account for the melanocortin-induced improvement in motor behavior of these injured rats. Similarly, dorsal root ganglia neurons subjected in vitro to cisplatin toxicity are protected to some degree by the ACTH 4—9 analog. This protection is specific in that it does not extend to Schwann cells or satellite cells, nor does it protect any of these cells from taxol toxicity. 

Cisplatin is highly toxic to dam mutants, suggesting a role for mismatch repair (44). Mismatch repair involves repair of mismatched bases at the replication fork. The dam mutants are not sensitive to /ranx-DDP, however (44). In contrast, another repair system called the adaptive response, used to repair bases damaged by alkylating agents, does not appear to be involved in mediating cisplatin toxicity (48). The adaptive response removes... 

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

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