Cisplatin is a platinum chemotherapeutic used in a variety of malignancies. The antineoplastic activity occurs from DNA cross-links and adducts, in addition to the generation of superoxide radicals. Nephrotoxicity is the most well-known and potentially most clinically significant toxicity. Unfortunately, the mechanism for cisplatin nephrotoxicity has not been completely elucidated; however, many theories have been developed. Other toxicities include gastrointestinal, myelosuppression, ototoxicity and neurotoxicity. Saline diuresis is currently the most accepted way to prevent cisplatin nephrotoxicity. Research has focused on pharmaceuticals and enzyme/molecular alterations as alternatives to long-term diuresis. No agents have currently been identified that can protect from all toxicities. Cisplatin has shown activity against osteosarcoma, transitional cell carcinoma, squamous cell carcinoma (SCC), melanoma, mesothelioma, carcinomatosis and germinal cell tumours in the dog. In the cat, cisplatin cannot be utilized because of fulminant pulmonary oedema that occurs at standard doses. Intralesional cisplatin has been utilized in horses for the treatment of SCC and sarcoids.

Cisplatin: a review of toxicities and therapeutic applications.

The chemotherapeutic cisplatin causes renal dysfunction and renal proximal tubular cell (RPTC) apoptosis. The goal of these studies was to examine the role of p53, caspase 3, 8, and 9, and mitochondria in the signaling of cisplatin-induced apoptosis. Cisplatin (50 microM) produced time-dependent apoptosis in RPTCs, causing cell shrinkage, a 50-fold increase in caspase 3 activity, a 4-fold increase in phosphatidylserine externalization, and 5- and 15-fold increases in chromatin condensation and DNA hypoploidy, respectively. Mitochondrial membrane potential and ATP levels did not change at any time during cisplatin exposure. Caspase 8 and 9 activities also did not increase during treatment. Cisplatin increased nuclear p53 expression 4 h after treatment, preceding both caspase 3 activation and chromatin condensation. Treatment with the p53 inhibitor alpha-2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-p-tolylethanone (PFT) before cisplatin exposure inhibited p53 nuclear expression at 4, 8, and 12 h and inhibited phosphatidylserine externalization and caspase 3 activation at 12 h. Neither DEVD-fmk nor ZVAD-fmk inhibited cisplatin-induced p53 nuclear expression. Both DEVD-fmk and ZVAD-fmk completely inhibited caspase 3 activity but, like PFT, partially inhibited cisplatin-induced chromatin condensation, annexin V labeling, and DNA hypoploidy after 24 h. These data demonstrate that at least 50% of cisplatin-induced apoptosis in RPTC is mediated by p53 and that p53 activates caspase 3 independently of either caspase 9 or 8 or mitochondrial dysfunction. Furthermore, 50% of cisplatin-induced RPTC apoptosis is independent of p53 and caspases 3, 8, and 9.

Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways.

The role of oxygen free radicals in cisplatin-induced acute renal failure in rats

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

The introduction of platinum compounds as antitumor agents has revived the significant clinical problem of nephrotoxicity caused by heavy metals. Cisplatin-induced nephrotoxicity has been shown to be dose-related in both animals and humans [57]; proximal renal tubular necrosis has been demonstrated in most animal species [72]. The major damage in humans has been observed in more distal parts of the proximal tubule or in the distal nephron segments [33]. Prolonged weekly injections in rats cause tubular atrophy of cortical nephrons, cystic dilatation of inner cortical or medullary tubules, and chronic renal failure due to tubulointerstitial nephritis [92]. Dobyan et al. [25] have located the lesion in the rat to the $3 segment of the proximal tubule in the outer stribe of the medulla. In rats, renal failure may be nonoliguric due to a renal concentrating defect [74]; the inhibition of vasopressin synthesis or release has also been proposed [12]. In early clinical trials with cisplatin, serious toxicity was encountered, mainly severe nausea, vomiting, neurotoxicity, ototoxicity and nephrotoxicity. Initial experience revealed that approximately 25% of the patients who received a single dose of cisplatin suffered reversible azotemia for 1-2 weeks following treatment [49]. Irreversible renal failure requiring dialysis has also been experienced, especially with large doses or multiple courses of treatment [39]. Single courses of 2 mg/kg or 75 mg/m 2 cisplatin are associated with nephrotoxicity in one-third of the patients treated [49]. The cellular mechanism of platinum nephrotoxicity is unknown. Levi et al. [54] have reported a decrease in protein-bound sulfhydryl groups in the renal tissue in rats prior to the development of frank renal failure. In vitro studies showed no direct interaction of platinum with sulfhydryl groups of cysteine or renal homogenates. The decrease in sulfhydryl groups was similar in magnitude in the outer medulla and cortex, whereas platinum concentrations were higher in the medulla. Cysteamine, penicillamine and N-acetylcystein offered no protection against experimental platinum nephrotoxicity [83]. There is evidence that the therapeutic efficacy of cisplatin increases with increasing dose [14, 38, 50, 66]. Higher doses of cisplatin also increase the vulnerability of

Douglas H. Chase

Papers

Cis-diamminedichlorplatinum-induced acute renal failure in the rat