Comparative analysis of cell injury after exposure to antitumor platinum derivatives in kidney tubular epithelial cells.
BACKGROUND
Platinum derivatives differ in effectiveness and safety. The purpose of this study is to compare differences in the mechanism of nephrotoxicity among these derivatives.


METHODS
LLC-PK(1) cells were used as a model of tubular epithelial cells. Cytotoxicity was evaluated by WST-1 assay, and cellular accumulation of platinum was examined by inductively coupled plasma mass spectrometer. As indexes of necrosis and apoptosis, lactate dehydrogenase release, DNA fragmentation and caspase 3 activation were examined.


RESULTS
In terms of cytotoxicity, the derivatives ranked in the order of oxaliplatin > cisplatin > nedaplatin > carboplatin, being comparable with that for the level of platinum accumulated in LLC-PK(1) cells. Lactate dehydrogenase release and DNA fragmentation were observed following treatment with all the derivatives, but were lowest for carboplatin. In terms of activating caspase 3, the order was cisplatin > nedaplatin > oxaliplatin > carboplatin.


CONCLUSIONS
Cytotoxicity by the derivatives was dependent on cellular accumulation of platinum and suggested to be mediated by apoptosis and necrosis; however, contributions differed among the derivatives.
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
Noriaki
N
Kitada
Kohji
K
Takara
Chihiro
C
Itoh
Tetsuya
T
Minegaki
Masayuki
M
Tsujimoto
Toshiyuki
T
Sakaeda
Teruyoshi
T
Yokoyama
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006836:Hydro-Lyases / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010984:Platinum / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine
D000970:Antineoplastic Agents; D010984:Platinum; D053148:Caspase 3; D006836:Hydro-Lyases; C045581:lactate dehydratase