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| CRITICAL SUBCELLULAR TARGETS OF CISPLATIN AND RELATED PLATINUM ANALOGS IN RAT RENAL PROXIMAL TUBULE CELLS |
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| Author(s): LEIBBRANDT MEI, WOLFGANG GHI, METZ AL, OZOBIA AA, HASKINS JR |
| Source: KIDNEY INTERNATIONAL Volume: 48 Issue: 3 Pages: 761-770 Published: SEP 1995 |
| Times Cited: 70 References: 26 |
| Abstract: The clinical usefulness of chemotherapeutic agents containing the platinum moiety is often limited by their nephrotoxicity. To investigate the mechanism of nephrotoxicity, and to assess the effects of platinum analogs on specific organelles and basal protein synthesis, biochemical and ultrastructural analyses were performed in rat renal proximal tubule cells (RPTCs). Neutral red (NR) uptake was used to measure lysosomal function, and conversion of MTT to formazan used to assess mitochondrial function. Despite their differential toxicity, cisplatin, carboplatin and CI-973 caused similar progressive inhibition of specific functions, suggesting they may share a common mechanism of nephrotoxicity. Protein synthesis was the earliest indicator of toxicity, followed by NR uptake and MTT conversion. Fluorescent probes for lysosomes (acridine orange) and mitochondria (rhodamine 123) confirmed that cisplatin's toxicity to RPTCs was delayed and cumulative. Condensation of nucleolar components and fragmentation of RER were observed in RPTCs treated for as little as two hours. Since the nucleolus is the site of ribosome biogenesis, the early inhibition of protein synthesis by cisplatin may arise from disruption of this region. In contrast, mitochondrial dysfunction and swelling were late-stage events, and are therefore unlikely to be the primary targets of nephrotoxic platinum compounds. |
| Document Type: Article |
| Language: English |
Addresses:
1. WARNER LAMBERT PARKE DAVIS, PARKE DAVIS PHARMACEUT RES, DEPT PATHOL & EXPTL TOXICOL, ANN ARBOR, MI 48105 USA |
| Publisher: BLACKWELL SCIENCE PUBL INC CAMBRIDGE, 238 MAIN ST, CAMBRIDGE, MA 02142 |
| Subject Category: Urology & Nephrology |
| IDS Number: RQ658 |
| ISSN: 0085-2538 |
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