Toxicity of cisplatin

A. Yonezawa, S. Masuda, K. Nishihara, I. Yano, T. Katsura, and K. Inui. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochem Pharmacol 70 1823-1831 (2005). 

Renal toxicity is the major potential toxicity of cisplatin. Severe nausea and vomiting that often accompany cisplatin administration may necessitate hospitalization. Cisplatin has mild bone marrow toxicity, yielding both leukopenia and thrombocytopenia. Anemia is common and may require transfusions of red blood cells. Anaphylactic allergic reactions have been described. Hearing loss in the high frequencies (4000 Hz) may occur in 10 to 30% of patients. Other reported tox-icities include peripheral neuropathies with paresthesias, leg weakness, and tremors. Excessive urinary excretion of magnesium also may occur. 

Studies in laboratory animals have shown that intravenous administration of a high dose of GSH (up to 500 mg/kg) within 30 min of cisplatin injection protects against cisplatin-induced neurotoxicity and nephrotoxicity. Subcutaneous injection of GSH or GSH monoisopropyl ester 2.5 h before injection of cisplatin also protected mice against nephrotoxicity and the acute lethal toxicity of cisplatin, although the GSH ester was far more effective than GSH itself. In these studies, treatment with GSH or GSH ester did not interfere with the antitumor effectiveness of cisplatin, which can be explained by the characteristics of uptake of GSH and cisplatin. GSH and cisplatin are cleared rapidly from the circulation. 

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of the parent compound cisplatin almost led to its abandonment, until Cvitkovic et al. introduced aggressive hydration, which prevented the development of acute renal failure [2] [3], As noted above, the toxicity of cisplatin was a driving force both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. 

The ability of bismuth subnitrate to reduce specifically the toxicity of cisplatin and adriamycin was ascribed to the fact that bismuth induces metallothionein by Naganuma and coworkers and Boogaard and coworkers . Naganuma and coworkers also found that preinduction of metallothionein by oral administration of bismuth subnitrate significantly decreased the lethal toxicity, cardiotoxicity and bone-marrow toxicity observed with a single subcutaneous injection of adriamycin. 

Ocular toxicity of cisplatin has been reported in a 47-year-old woman who experienced rapid uncontrollable eye movements associated with hypomagnesemia and hypocalcemia in the presence of renal tubular damage (123). 

In experiments in mice, the trace element selenium, which interacts with heavy metals, reduces the renal, intestinal, hepatic, and hematological toxicity of cisplatin without affecting its antitumor activity (198). 

Lind MJ, McGregor J, Timms MS, Brown D, Palmer P. Comparative toxicity of cisplatin, carboplatin (CBDCA) and iproplatin (CHIP) in combination with cyclophosphamide in patients with advanced epithelial ovarian cancer. Eur J Cancer Clin Oncol 1988 24(9) 1471-9. 

An impressive list of compounds has been used to decrease cisplatin nephrotoxicity [ANF, glycine, diethyldithiocarbamate, calcium channel blockers, cimetidine, sodium thiosulphate, glutathione, other sulfidryl compounds,. ..]. Among them only sodium thiosulphate has received a significant clinical application and has been reported to reduce the renal toxicity of cisplatin administered locally by either the intra-arterial, intra-peritoneal or intrathoracic routes [50, 51]. However, controversies still exists as to the effect of sodium thiosulphate on cisplatin antitumor activity. Thus sodium thiosulphate may be most useful in combination with intraperitoneal cisplatin where it confers renal protection without altering local effects of cisplatin [51]. 

Khrunin AV, Moisseev A, Gorbunova V, Limborska S (2010) Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. Pharmacogenomics J 10 54-61... 

The cytotoxic form of cisplatin is the aquated species, in which hydroxyl groups or water molecules replace the two chloride groups. This reaction occurs readily in low concentrations of chloride, such as the concentrations present within cells, and produces a positively charged compound that can react with DNA. The aquated species is responsible for both the efficacy and toxicity of cisplatin. Carboplatin also undergoes aquation, but at a slower rate. Oxaliplatin becomes active when the oxalate ligand is displaced in physiologic solutions. ... 

Cisplatin and related compounds have also been evaluated in the management of metastatic melanoma. The effectiveness of platinum compounds as single agents is limited, with response rates reported to be less than 10%. The toxicities of cisplatin can be problematic, and include acute and delayed nausea and vomiting, renal toxicity, and neurotoxicity. 

Toxicity. The toxicity of cisplatin has been studied both in large animals such as dogs and monkeys [46] and in small animals as a basis for screening... 

Amifostine is an organic thiophosphate cytoprotective agent that can reduce the toxicity of cisplatin. It binds to and thereby detoxifies reactive metabolites of cisplatin. It scavenges reactive oxygen species generated by exposure to cisplatin radiation. 

Pulmonary toxicity with bleomycin is an established reaction with a potentially serious, sometimes fatal, outcome. Concurrent use should be very closely monitored and renal function checked. One of the problems is that levels of creatinine may not accurately indicate the extent of renal damage both during and after cisplatin treatment. The renal toxicity of cisplatin may also develop rapidly. Other toxic effects on the vascular system can also occur. 

The renal toxicity of cisplatin is potentiated by aminoglycoside antibacterials such as gentamicin and tobramycin. Extra care is required in patients treated with cisplatin requiring these antibacterials. In one retrospective analysis in patients taking cisplatin, hearing loss was not associated with the concurrent use of ototoxic drugs, including tobramycin. 

Bismuth and zinc are known to be potent inducers of renal metallothionein (MT) synthesis, and pretreatment with bismuth significantly reduces the renal and lethal toxicity of cisplatin without affecting its anticancer activity in human patients [146], The protection probably involves Bi induction of metallothionein synthesis. UV and NMR studies have shown that Bi° binds very strongly... 

D. G. (2009). Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. J. Gene Med. ii, 160-168. 

Adams, C., McCarthy, H.O., Coulter, J.A., Worthington, J., Murphy, C., Robson, T., and Hirst, D.G. (2008). Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. J. Gene Med. (Dec 8) (Epub ahead of print). 

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