Cisplatin is used widely in the treatment of a large number of carcinomas. The clinical use of cisplatin, however, can be complicated by myelotoxicity, ototoxicity and intestinal toxicity; we review briefly cisplatin nephrotoxicity. The principal route of its excretion is via the kidney, and accumulation of cisplatin in the renal cortex has been demonstrated. Three to five days following administration of cisplatin to rats, degenerative changes appear in the proximal tubule, including cytoplasmic vacuolization, tubular dilatation and pyknotic and hydropic degeneration. A decrease in renal plasma flow was observed very early on in patients receiving cisplatin at a dose of 20 mg/m2 over a period of 4 h, and an increase in urinary enzymes occurred rapidly. Hypomagnesaemia, hypocalcaemia and hypokalaemia were frequent. The mechanism of cisplatin nephrotoxicity remain unclear. Biotransformation of cisplatin could play an important role; a decrease in sulphydryl groups in the kidney may be a primary event, and reactive metabolites may be formed. The incidence of cisplatin nephrotoxicity has been observed to decrease when patients are prehydrated, and it was proposed recently that administration of a calcium blocker might reduce the nephrotoxic effects of cisplatin. The clinical recommendations are to avoid rapid cisplatin infusion rates (over 1 mg/kg per hour) and to induce hydration at least during and after cisplatin administration. New compounds with the same or better antitumour activity and less toxicity should be prepared. At present, carboplatin appears to be preferable to cisplatin because of the reduced incidence of untoward effects.

Celiptium is an ellipticine derivative with renal toxic side effects. It has recently been characterized as a lipid overload in proximal tubular cells where loss of total phospholipids (in particular phosphatidylethanolamine) and of polyunsaturated fatty acids are linked to the accumulation of unsaturated free fatty acids and aldehydes. A time course study of celiptium-induced peroxidative damage showed that a single dose of 40 mg/kg of celiptium induced no change in total or individual phospholipids of rat renal cortex. On the other hand, free fatty acids and thiobarbituric acid reactive substances increased as early as 1 hr after celiptium injection. 4-Hydroxynonenal (4-HNE) also increased whereas polyunsaturated fatty acids levels decreased at 6 and 24 hr. After 24 hr no change was detected in microsomal phospholipids. In contrast, the brush-border membranes showed alterations such as decrease in total phospholipids and polyunsaturated fatty acids levels accompanied by increase in aldehydes. It appears that peroxidative damage occurs in brush-border membranes of celiptium-treated rat kidneys with preferential losses of phosphatidylethanolamine (PE, 30%) and phosphatidylcholine (PC, 14%).

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A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.