Methods of reduction of cisplatin nephrotoxicity.

Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, phar­ macological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, pro­ duced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of de­ velopment of organoplatinum analogs yielding congeners with less nephro­ toxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or revers­ ing heavy metal nephrotoxicity is suggested. Background and General Considerations: Pharmacology, Toxicology, and Pharmacokinetics Cisplatin* is effective against a number of animal tumor systems.13,14,73,97 In man, it is especially active in the treatment of testicular cancer, and also in lymphomas, Hodgkin’s disease, head and neck can­ cers, thyroid, bladder, ovarian, and en­ dometrial cancer.22 Cisplatin, a neutral com pound in plasm a, appears to be * Platinol®, Bristol Laboratories. aquated intracellularly to form a pos­ itively charged platinum species capable of interacting with nucleophilic sites with intrastrand and interstrand cross-linking of biomacromolecules.50,99 Renal pathol­ ogy with functional impairment is the main toxic com plication of c isp latin therapy, but other sites of toxicity in hum an patien ts include the gastro­ intestinal system (nausea, vomiting and diarrhea, and rarely mild transient eleva­ tions of serum glutamic oxaloacetic trans­ aminase and serum glutamic pyruvic