Evaluation of the effect of glutathione on cisplatin antitumor activity             and kidney injury at different administration times.
Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most potent             anticancer drugs. However, the therapeutic value of CDDP is greatly compromised             by its dose-limiting nephrotoxicity. This study was performed to investigate whether             reduced glutathione (GSH) was able to reduce the kidney injury induced by CDDP             and whether it affected the anticancer activity of CDDP in vivo and in vitro.             In in vivo experiments, mice were divided into five groups: control, CDDP only             and three GSH treatment groups. Blood samples were collected 72 h after CDDP administration             to determine the levels of blood urea nitrogen (BUN) and plasma creatinine (Cr).             In addition, we examined antioxidative parameters, malondialdehyde (MDA) levels             and histopathological changes in the kidney. In order to investigate whether GSH             affected the anticancer activity of CDDP, we performed a sulforhodamine B (SRB)             assay to determine the anti-proliferative effect in three tumor cell lines of             treatment with CDDP alone or combined with GSH and examined the cell morphology.             The results revealed that GSH decreased the BUN and Cr levels in plasma, ameliorated             the pathological changes induced by CDDP and enhanced the endogenous antioxidant             capacities in all three GSH groups. Furthermore, GSH significantly inhibited the             growth of the three tumor cell lines when combined with CDDP and did not affect             the inhibitory effect of CDDP on the carcinoma cell proliferation. In addition,             we found no differences among the three GSH groups. These findings suggest that             GSH is able to attenuate the nephrotoxicity induced by CDDP, not only when administered             prior to CDDP, but also when administered at the same time as or subsequent to             CDDP administration, without affecting the anticancer activity of CDDP. Thus,             the administration of GSH is a promising approach for attenuating the nephrotoxicity             caused by CDDP.
Department of Cell Biology, Binzhou Medical University, Yantai, Shandong, PR China. bzmcxyy@yahoo.cn
Yan-Yan
YY
Xu
Na
N
Jiang
Tong-Shen
TS
Liu
Hui-Qing
HQ
Qu
Tian
T
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D005978:Glutathione / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D061986:MCF-7 Cells; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D013482:Superoxide Dismutase / Q000378:metabolism; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D008315:Malondialdehyde; D003404:Creatinine; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D002945:Cisplatin