Methods of reduction of cisplatin nephrotoxicity.
1981
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
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