Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity.
The present study examined the influence of cimetidine on the nephrotoxicity and antitumor effects of cisplatin in vitro and in vivo. When the serum concentration of cimetidine was maintained over 20 µg/ml for 4 h by bolus and continuous intravenous infusion, cimetidine prevented nephrotoxicity of cisplatin without influencing antitumor activity. Cimetidine and the antioxidant N-acetylcysteine (NAC) significantly inhibited the in vitro growth inhibition of cisplatin in cells originating from the kidney, but not in SOSN2 osteosarcoma cells. Cimetidine (1 mM) also did not influence platinum concentration in the cells, regardless of whether the organic cation transporter 2 (OCT2) was expressed. Cisplatin did induce reactive oxygen species (ROS) in the KN41 kidney cell line and cimetidine and NAC significantly reduced ROS production. However, cisplatin did not produce ROS in osteosarcoma cells. From these results, cimetidine clearly inhibits nephrotoxicity induced by cisplatin without any influence on the antitumor activity of cisplatin on osteosarcoma in vitro and in vivo.
Department of Medicinal Informatics, Graduate School of Medical Science, Kanazawa University, 13–1 Takara-machi, Kanazawa 920–8641, Japan.
Hiromu
H
Katsuda
Mariko
M
Yamashita
Hideyuki
H
Katsura
Jia
J
Yu
Yoshihiro
Y
Waki
Naoto
N
Nagata
Yoshimichi
Y
Sai
Ken-Ichi
K
Miyamoto
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002927:Cimetidine / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012076:Renal Agents / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D017382:Reactive Oxygen Species; D012076:Renal Agents; D010984:Platinum; D002927:Cimetidine; D002945:Cisplatin; D000111:Acetylcysteine