Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen.
2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with platinum compounds. The influence of ebselen on cis-diamminedichloroplatinum(II) (cisplatin)-induced nephrotoxicity in mice was assessed, using single doses of both compounds. Ebselen prevented cisplatin-induced elevations of blood urea nitrogen and serum creatinine levels and morphological kidney damage in BALB/c mice. This protective effect of ebselen was dose dependent: at a cisplatin dose of 14.5 mg/kg, maximal protection was achieved when a single dose of 10 mg of ebselen/kg was administered 1 h before cisplatin. Administration of ebselen, 10 mg/kg, 1 h after cisplatin also protected against severe nephrotoxicity. Treatment with ebselen did not reduce the antitumor activity of cisplatin against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. However, this reduction of cisplatin-induced nephrotoxicity would be of little clinical value if it was achieved at toxic doses of ebselen. Ebselen, 10 mg/kg, did not induce blood urea nitrogen, serum creatinine, serum glutamic pyruvate transaminase, or serum glutamic oxalate elevations in the mice. These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug. The present results indicate that ebselen may provide protection against cisplatin-induced nephrotoxicity, when it is given before or after cisplatin. This might open new perspectives in cancer chemotherapy.
Department of Radiochemistry, Interfaculty Reactor Institute, Delft, The Netherlands.
G S
GS
Baldew
J G
JG
McVie
M A
MA
van der Valk
G
G
Los
J J
JJ
de Goeij
N P
NP
Vermeulen
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D001393:Azoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D054833:Isoindoles; D007668:Kidney / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016566:Organoselenium Compounds; D010954:Plasmacytoma / Q000188:drug therapy; D012643:Selenium / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D012643:Selenium; D002945:Cisplatin