Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats
Introduction
Cisplatin is one of the most active antineoplastic drugs that is particularly used for the treatment of ovarian, testicular and head and neck cancers Van Basten et al., 1997, Thigpen et al., 1994. In spite of its significant antitumor activity, the clinical use of cisplatin is often limited by its undesirable side effects, nephrotoxicity and neurotoxicity being the most severe and dose-limiting ones Mollman et al., 1988, Screnci and McKeage, 1999. Nevertheless, other less frequent toxic effects, as hepatotoxicity, which is frequently observed after administration of high doses of cisplatin, can alter the clinical situation of patients Cersosimo, 1993, Cavalli et al., 1978, Pollera et al., 1987. Many efforts have been made to improve the therapeutic index of cisplatin using pharmacological strategies, such as the administration of chemoprotectors, intensive hydration and hypertonic saline Skinner, 1995, Anand and Bashey, 1993, Pinzani et al., 1994. Unfortunately, some of the compounds used as chemoprotectors also inhibit the antitumor activity of cisplatin, while other therapeutic strategies were not completely efficient in reducing the dose-limiting nephrotoxicity Aamdal et al., 1987, Jones et al., 1991, Abe et al., 1990, Pinzani et al., 1994.
In our previous studies Esposito et al., 1996, Viale et al., 2000, we found evidence for a chemoprotective effect of procainamide hydrochloride against cisplatin-induced nephrotoxicity in mice and rats. This class I antiarrhythmic drug was able to reduce the weight loss and to protect mice against death induced by lethal doses of cisplatin. The combination therapy of procainamide hydrochloride and cisplatin resulted in a significant increase in survival, when drugs were administered either simultaneously i.p. or through different routes of administration (i.p. and i.v.). In rats, procainamide hydrochloride protected from nephrotoxicity when given simultaneously or from 1 h before to 1 h after cisplatin, as confirmed by plasma urea nitrogen and creatinine levels and microscopical analysis of kidney tissue. Moreover, procainamide hydrochloride decreased the urinary excretion of platinum and increased platinum concentration in the kidney of rats. Based on the capability of procainamide hydrochloride to react with cisplatin and its hydrolysis products, we proposed that the antiarrhythmic drug could accumulate in the kidney and coordinate with the anticancer drug forming a less toxic platinum coordination complex, which renders rats less susceptible to cisplatin-induced toxicity.
In the present paper, we studied the protective activity of procainamide hydrochloride on cisplatin-induced hepatotoxicity, in particular, on the level of cellular damage of liver parenchyma. This was determined by measuring plasma glutamic oxalacetic and glutamic pyruvate transaminases, γ-glutamyl transpeptidase and by histochemical analysis of liver tissue. The analysis in liver of total platinum, platinum–DNA adducts, percent interstrand cross-links, procainamide concentration and intracellular platinum distribution was also performed.
Section snippets
Chemicals
Cisplatin and procainamide hydrochloride were purchased from Sigma (St. Louis, MO, USA). When the two drugs were administered to rats as single agents, cisplatin was dissolved in normal saline (0.9% NaCl), while the modulating agent was diluted in distilled water to prepare a 1.25% solution. Since dissolving procainamide hydrochloride in 0.9% NaCl increases the chloride anion concentration of the solution, when both drugs were administered together, they were diluted in appropriate NaCl
Evidence of liver tissue damage
In our experiments, the high dose of cisplatin (7.5 mg/kg) administered to rats caused an evident liver damage characterized by a significant increase of glutamic oxalacetic transaminase [385±105 vs. 143±20 IU/ml in controls] and γ-glutamyl transpeptidase [5.8±1.3 vs. 0.8±0.8 IU/ml in controls] plasma activities. A slight, but not significant, elevation of plasma glutamic pyruvate transaminase [83±27 vs. 50±1 IU/ml in controls] was also observed (Table 1). It is of note that the treatment with
Discussion
It is known that cisplatin is significantly taken up in human liver (Smith and Taylor, 1974); nevertheless, hepatotoxicity rarely occurs. For this reason, this toxic effect has not received much attention and only few articles deal with this aspect. Generally, liver toxicity of cisplatin is characterized by mild to moderate elevation of serum transaminases and, less frequently, by a mild elevation of serum alkaline phosphatase, lactate dehydrogenase, bilirubin and γ-glutamyl transpeptidase
Acknowledgements
This paper is dedicated to Dr. Mauro Esposito who first had the idea to use procainamide as chemoprotector against cisplatin-induced nephrotoxicity. We thank Prof. M. Novi for the critic revision of this paper. This work was in part supported by “Lega Italiana per la Lotta contro i Tumori”, Section of Sanremo, Italy.
References (32)
- et al.
Some procedures to reduce cis-platinum toxicity reduce antitumour activity
Cancer Treat. Rev.
(1987) - et al.
Platinum(II) complexes containing iminoethers: a trans platinum antitumor agent
Chem. Biol. Interact.
(1995) - et al.
Effect of antiarrhythmic drug procainamide on the toxicity and antitumor activity of cis-diamminedichloroplatinum(II)
Toxicol. Appl. Pharmacol.
(1996) - et al.
DNA typing for class II HLA antigens with allele-specific or group-specific amplification: I. Typing for subsets of HLA-DR4
Hum. Immunol.
(1990) - et al.
Relative effectiveness of some compounds for the control of cisplatin-induced nephrotoxicity
Toxicology
(1991) - et al.
Metallothionein (MT)-null mice are sensitive to cisplatin-induced hapatotoxicity
Toxicol. Appl. Pharmacol.
(1998) Current concepts on hepatic transport of drugs
J. Hepatol.
(1987)- et al.
Platinum neurotoxicity: clinical profiles, experimental models and neuroprotective approaches
J. Inorg. Biochem.
(1999) - et al.
Current concept about testicular cancer
Eur. J. Surg. Oncol.
(1997) - et al.
Cisplatin-induced nephrotoxicity in vitro: increases in cytosolic calcium concentration and the inhibition of cytosolic and mitochondrial protein kinase C
Toxicol. Lett.
(1996)
Inactivation of cis-diamminedichloroplatinum(II) in blood by sodium thiosulphate
Oncology
Newer insights into cisplatin nephrotoxicity
Ann. Pharmacother.
Mitochondrial injury: an early event in cisplatin toxicity to renal proximal tubules
Am. J. Physiol.
Synthesis and antitumor activity of a new cis-diammineplatinum(II) complex containing procaine hydrochloride
Anticancer Res.
Cisplatin-induced hepatic toxicity
Cancer Treat. Rep.
Hepatotoxicity associated with cisplatin chemotherapy
Ann. Pharm.
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