Cisplatin nephrotoxicity

doi:10.1016/S0270-9295(03)00089-5

Seminars in Nephrology

Volume 23, Issue 5, September 2003, Pages 460-464

https://doi.org/10.1016/S0270-9295(03)00089-5 Get rights and content

Abstract

Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure. The kidney accumulates cisplatin to a higher degree than other organs perhaps via mediated transport. Functionally, reduced renal perfusion and a concentrating defect characterize its nephrotoxicity, whereas morphologically necrosis of the terminal portion of the proximal tubule and apoptosis predominantly in the distal nephron characterize its effects on cell fate. Among the earliest reactions of the kidney to cisplatin is the activation of the MAPK cascade and molecular responses typical of the stress response. Repression of genes characteristic of the mature phenotype of the kidney, especially those serving transport function of the kidney, is also prominent. Metabolic responses, cell cycle events and the inflammatory cascade seem to be important determinants of the degree of renal failure induced by cisplatin. Manipulation of these responses may be exploited to reduce its toxicity clinically.

Section snippets

Renal uptake and metabolism of cisplatin

The kidney accumulates and retains platinum to a greater degree than other organs and is the principal excretory organ for injected cisplatin.3 In the rat, the kidney excretes the drug rapidly within the first hour of its administration by a process consisting predominantly of glomerular filtration, with a minor component of secretion.4, 5, 6 There is no evidence of tubular reabsorption, suggesting that the kidney accumulates cisplatin by peritubular uptake.5 The uptake of cisplatin by the

Role of the mitogen activated protein kinases in cisplatin nephrotoxicity

Cisplatin induces a prominent immediate early gene response in the kidney including expression of the stress-related proteins c-jun and junD.17 Cellular stress, including DNA-damaging chemotherapeutic drugs, activates 2 related signaling pathways: the stress-activated protein kinase, also know as Jun N-terminal kinase (JNK), and the extracellular regulated kinase (ERK)-mitogen-activated protein kinase.18 Targets of stress-activated protein kinase/JNK include c-Jun and JunD components of the

References (49)

U. Schaeppi et al.
Cis-dichlorodiammine platinum II (NSC 119875)Preclinical toxicologic evaluation of intravenous injections in dogs, monkeys and mice
Toxicol Appl Pharmacol
(1973)
R. Safirstein et al.
Uptake and metabolism of cisplatin by rat kidney
Kidney Int
(1984)
R.L. Safirstein et al.
Mutagenic activity and identification of excreted platinum in human and rat urine and rat plasma after administration of cisplatin
Cancer Lett
(1983)
B. Rosenberg
CisplatinIts history and possible mechanism of action
R.K. Barr et al.
The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs)
Int J Biochem Cell Biol
(2001)
C.R. Weston et al.
The JNK signal transduction pathway
Curr Opin Genet Dev
(2002)
B.W. Zanke et al.
The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat
Curr Biol
(1996)
I. Sanchez-Perez et al.
Lack of c-Jun activity increases survival to cisplatin
FEBS Lett
(1999)
G.P. Kaushal et al.
Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells
Kidney Int
(2001)
S. Kharbanda et al.
Translocation of SAPK/JNK to mitochondria and interaction with Bcl-xL in response to DNA damage
J Biol Chem
(2000)

G. Nowak

Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells

J Biol Chem

(2002)

V. Mavichak

Studies on the pathogenesis of cisplatin-induced hypomagnesaemia in rats

Kidney Int

(1985)

J. Hayakawa et al.

Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line

J Biol Chem

(1999)

X. Wang et al.

Requirement for ERK activation in cisplatin-induced apoptosis

J Biol Chem

(2000)

J.C. Gonzales-Vitale et al.

The renal pathology in clinical trials of cis-platinum (II) diamminedichioride

Cancer

(1977)

C.L. Litterst et al.

Plasma levels and organ distribution of platinum in the rat, dog, and dog fish following intravenous administration of cis-DDP(II)

J Clin Hemat Oncol

(1977)

R. Safirstein

Renal disposition and metabolism of liganded platinumImplications to toxicity

Fed Proc

(1980)

C. Jacobs

Renal handling of cis-diammine dichloroplatinum (II)

Cancer Treat Rep

(1980)

R. Safirstein