Differential toxicity of cisplatin, carboplatin, and CI-973 correlates with cellular platinum levels in rat renal cortical slices.
The differential toxicity of the platinum-containing compounds, cisplatin, carboplatin, CI-973, and transplatin, was investigated in renal cortical slices over a 24-hr period. Platinum accumulation was measured to assess whether platinum levels correlated with inhibition of specific cell functions (accumulation of organic ions, protein synthesis) or potassium loss. The earliest indicator of toxicity was decreased accumulation of the organic anion, para-aminohippuric acid (PAH), which preceded a decrease in the accumulation of the organic cation, tetraethyl-ammonium (TEA), and protein synthesis. Cisplatin (1 mM) and CI-973 (3 mM) treatment reduced PAH accumulation within 2 hr; carboplatin (3 mM) decreased PAH at 6 hr. TEA accumulation was absent in slices incubated for 6 hr or longer in 1 mM cisplatin, or for 24 hr in 3 mM carboplatin or CI-973. Protein synthesis was inhibited 80, 75, and 87% in slices treated for 24 hr with 100 microM cisplatin, 1 mM carboplatin, and 1 mM CI-973, respectively, compared to control. Intracellular potassium levels, which decreased between 6 and 24 hr, were the least sensitive indicator of cell damage. Transplatin, which lacks antitumor activity and is nonnephrotoxic in vivo, effectively decreased protein synthesis, intracellular potassium, and organic ion accumulation in rat renal cortical slices in vitro. The concentration of slice-associated platinum following treatment with cisplatin, carboplatin, CI-973, and transplatin increased with time and concentration. Inhibition of protein synthesis and loss of intracellular potassium correlated with increased total cellular platinum, indicating that platinum compounds negatively affect cell function and viability. The relative toxicity of these compounds in rat renal cortical slices was cisplatin = transplatin > CI-973 > carboplatin.
Leibbrandt
M E
ME
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan, USA.
Wolfgang
G H
GH
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000737:chemistry* / Q000166:cytology; D008297:Male; D010984:Platinum / Q000032:analysis*; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D011506:Proteins; C055425:NK 121; D010984:Platinum; D016190:Carboplatin; D002945:Cisplatin