The nephrotoxicity of cisplatin

Cisplatin is a cancer chemotherapeutic agent whose clinical use is complicated by its dose related kidney toxicity. Since the histopathological profile of cisplatin nephrotoxicity appears similar to that of other heavy metals, it has been commonly presumed that cisplatin nephrotoxicity is related to the platinum moiety. However, the delayed time course and development of cisplatin nephrotoxicity is not characteristic of heavy metal nephropathy. Furthermore, cisplatin nephrotoxicity is stereospecific to the cis and not the trans isomer, indicating that the platinum atom is not the proximate nephrotoxicant. It is likely that a metabolite of cisplatin, possibly an aquated and/or hydroxylated complex, mediates the nephrotoxicity of cisplatin.     

Mechanism of cisplatin nephrotoxicity

cis-Diamminedichloroplatinum II (cisplatin) is widely used in cancer treatments. Renal dysfunction is the major toxic effect of this drug. Micropuncture studies suggest that cisplatin reduces single-nephron glomerular filtration rate (GFR) and causes a significant backleak of inulin across the renal tubule. Pathological alterations are localized to the S3 segment of the proximal tubule situated in the outer stripe of the outer medulla. Renal clearance studies in humans demonstrate that the free platinum clearance exceeds the GFR, which suggests that cisplatin or a platinum metabolite is actively secreted by the kidney. Studies with renal cortex slices indicate that platinum is accumulated by renal tissue against a concentration gradient. This uptake is blocked by metabolic inhibitors and the organic base triethanolamine. Heavy metals are thought to produce renal damage because of interaction with renal sulfhydryl (SH) groups. After cisplatin administration to rats, total renal SH groups decreased by 14% owing to a decrease of protein-bound SH groups. The greatest decline of SH groups occurred in the mitochondrial and cytosolic fractions. These fractions also had the highest platinum concentrations. These results suggest that the nephrotoxic effects of cisplatin may be related to depletion of SH groups, but a cause and effect relationship has not been definitively established.     

Naringenin attenuates cisplatin nephrotoxicity in rats

The effect of naringenin (NAR), a naturally occurring citrus flavanone, on the acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5 days before cisplatin single i.v. injection, produced significant protection of renal function. NAR reduced the extent of cisplatin-induced nephrotoxicity, as evidenced by significant reduction in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione S-transferase (GST) activity, and increased creatinine clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and GST activity were markedly improved by NAR. Cisplatin-induced alterations in renal cortex antioxidant defense system were greatly prevented by NAR. In cisplatin-NAR combined treatment group, antioxidant enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin treated group. Platinum renal content was not affected by NAR treatment. The results provide further insight into the mechanisms of cisplatin-induced nephrotoxicity and confirm the antioxidant potential of NAR.     

Pharmacological blockade of the nephrotoxicity of cisplatin in rats

Cisplatin injection (0.5 mg/100 g body weight) induced 5 days later an increase in serum urea concentration from 3.31 +/- 0.67 to 47.1 +/- 8.68 mg/ml and diuresis decrease following water loading test. Ethacrynic acid, furosemide, paraaminohippurate pre-injections prevented cisplatin nephrotoxicity. The decrease in cisplatin nephrotoxicity took place when furosemide was administered before or 3 h after cisplatin injection; 6 h after cisplatin injection furosemide was not effective. The results suggest that pharmacological blockade of cisplatin nephrotoxicity depends on the drug penetration into secreting cells of proximal tubules.     

Renin-angiotensin system inhibitors combined with cisplatin exacerbate cisplatin-induced nephrotoxicity in mice

IntroductionWe previously reported that the concomitant use of enalapril and telmisartan exacerbates the risk of cisplatin (CDDP)-induced acute renal dysfunction compared to other antihypertensive drugs in mice. Thus, in the current study, we investigated the risk of developing chronic kidney disease following repeated concomitant use of CDDP and antihypertensive drugs.Materials and MethodsMale BALB/c mice were divided into 12 groups: (1) Control group (untreated), (2) CDDP group (7 mg/kg, CDDP), (3) AML group (5 mg/kg, amlodipine), (4) ENA group (2.5 mg/kg, enalapril), (5) TEL group (10 mg/kg, telmisartan), (6) LOS group (10 mg/kg, losartan), (7) CDDP+AML group (5 mg/mL, AML), (8) CDDP+ENA group (2.5 mg/kg, ENA), (9) CDDP+LowENA group (1.25 mg/kg, ENA), (10) CDDP+TEL group (10 mg/kg, TEL), (11) CDDP+LowTEL group (5 mg/kg, TEL), and (12) CDDP+LOS group (10 mg/kg, LOS). CDDP was administered intraperitoneally four times every 7 days, and each antihypertensive drug was administered orally from day 3 before CDDP administration until day 24 (six times a week). The degree of renal damage was assessed. The nephrotoxicity of each individual was evaluated by measuring serum creatinine and blood urea nitrogen levels. The degrees of renal fibrosis and epithelial-mesenchymal transition were also examined in kidney tissue sections.Results and DiscussionThe results suggest that combinatorial treatment of CDDP and renin-angiotensin system inhibitors, particularly ENA and TEL, may exacerbate CDDP-induced nephrotoxicity. This study clearly demonstrates the need for large-scale clinical studies to construct treatment regimens that do not interfere with the therapeutic intensity of CDDP.     

Renal immunolocalization of kallikrein in cisplatin nephrotoxicity in rats

Summary Treatment of rats with cisplatin (4 mg kg^-1body wt i.p. injection) induced variations of urinary kallikrein excretion (UKE). Three phases were observed: a transient increase of UKE one day after injection, followed by a decrease up to 10 days suggesting an altered biosynthesis and a recovery phase with return to normal control values, 21 days after injection. Early morphological lesions were observed in proximal tubule cells on day 1; severe changes and tubular necrosis were observed in the following days. Less marked changes were also present in distal tubules but the vacuolated and desquamated cells appeared in the lumen of the tubules. By immunocytochemical methods, kallikrein was observed in connecting tubule cells, but also in some proximal tubule cells and along the endothelial side of the glomerular basement membrane and urinary space of glomeruli. An intense labelling was present in desquamated epithelial cells in dilated lumen of tubules. This study provides evidence of the presence of immunoreactive kallikrein in the glomerulus, already reported during acute failure, and confirms the use of urinary kallikrein measurements as a useful non-invasive index to assess a possible nephrotoxic effect at the distal level.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage

AimsCisplatin (CP) promotes increased production of reactive oxygen species, which can activate p38 mitogen activated protein kinases (p38 MAPKs) leading to apoptosis and increased expression of proinflammatory mediators that intensify the cytotoxic effects of CP. We investigated the effect of the treatment with SB203580, a p38 MAPKs inhibitor, on oxidative stress, on the oxidation-associated signal, p38 MAPK and on apoptosis in CP-injected rats, starting after the beginning of the renal damage.Main methodsRats (n = 21) were injected with CP (5 mg/kg, i.p.) and 3 and 4 days after some of them (n = 8) were treated with SB203580 (0.5 mg/kg, i.p.). Controls (n = 6) received saline (i.p.). Two or five days after saline or CP injections, plasma creatinine, urinary volume, sodium and potassium fractional excretions, blood urea nitrogen and urinary lipid peroxidation were measured. The kidneys were removed for histological, apoptosis, immunohistochemical and Western blot studies.Key findingsCP caused abnormalities in kidney functions and structure associated with raised urinary peroxidation levels and higher number of apoptotic cells in the outer medulla. The immunostaining studies showed increased numbers of macrophages/monocytes and p-p38 MAPKs positive cells in the renal outer medulla. The increase of p-p38 MAPKs expression was confirmed by Western blot analysis. All of these alterations were attenuated by treatment with SB203580.SignificanceThese data suggest that the beneficial effect of SB203580 on CP-induced renal damage might be related, in part, to the blockade of p38 MAPK activation with reduction of the inflammatory process, oxidative stress and apoptotic cell death.     

Differential effects of tannic acid on cisplatin induced nephrotoxicity in rats

Cisplatin is a widely used antineoplastic drug. Major drawback of cisplatin therapy is its nephrotoxicity. The objective of this study was to check the effect of tannic acid on cisplatin induced nephrotoxicity. Post-treatment of tannic acid prevents cisplatin (5mg/kg) induced nephrotoxicity and decreases poly(ADP-ribose) polymerase cleavage, phosphorylation of p38 and hypoacetylation of histone H4. In contrast, co-treatment of tannic acid potentiates the nephrotoxicity. Comparative nephrotoxicity studies show that co-treatment of tannic acid with reduced dose of cisplatin (1.5mg/kg) developed almost similar nephrotoxicity. MALDI protein profiling of plasma samples provides indirect evidence that tannic acid co-treatment increases bioavailability of cisplatin.     

Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase

Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it is also a potent nephrotoxicant. Given that there have been no significant advances in our ability to clinically manage acute renal failure since the advent of dialysis, the development of novel strategies to ablate nephrotoxicity would represent a significant development. In this study, we investigated the ability of an inhibitor of soluble epoxide hydrolase (sEH), n-butyl ester of 12-(3-adamantan-1-yl-ureiido)-dodecanoic acid (nbAUDA), to attenuate cisplatin-induced nephrotoxicity. nbAUDA is quickly converted to AUDA and results in maintenance of high AUDA levels in vivo. Subcutaneous administration of 40 mg/kg of nbAUDA to C3H mice every 24 h resulted in elevated blood levels of AUDA; this protocol was also associated with attenuation of nephrotoxicity induced by cisplatin (intraperitoneal injection) as assessed by BUN levels and histological evaluation of kidneys. This is the first report of the use of sEH inhibitors to protect against acute nephrotoxicity and suggests a therapeutic potential of these compounds.     

Protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats

The effect of aminoguanidine (AG) on nephrotoxicity induced by cisplatin (CDDP) was investigated. A single dose of CDDP (7.5 mg/kg i.p.) induced nephrotoxicity, manifested biochemically by a significant elevation in serum urea, creatinine and a severe decrease in serum albumin. Moreover, marked increases in kidney weight, urine volume and urinary excretion of albumin were observed. Nephrotoxicity was further confirmed by a significant decrease in glutathione-S-transferase (GST, E.C. 2.5.1.18), glutathione peroxidase (GSH-Px, E.C. 1.11.1.9) and catalase (E.C. 1.11.1.6) and a significant increase in lipid peroxides measured as malondialdhyde (MDA) in kidney homogenates. Administration of AG (100 mg/kg per day p.o.) in drinking water 5 days before and 5 days after CDDP injection produced a significant protection against nephrotoxicity induced by CDDP. The amelioration of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations. In addition, AG tended to normalize decreased levels of serum albumin. Urine volume, urinary excretions of albumin and GST and kidney weight were significantly decreased. Moreover, AG prevented the rise of MDA and the reduction of GST and GSH-Px activities in the kidney. These results suggest that AG has a protective effect on nephrotoxicity induced by CDDP and it may therefore improve the therapeutic index of CDDP.     

Renoprotective effects of montelukast in an experimental model of cisplatin nephrotoxicity in rats

Renal toxicity is one of the most severe complications that can occur with cisplatin (CIS) administration in cancer patients. Montelukast (ML) renoprotective outcome contrary to CIS‐drawn nephrotoxicity remains obscure. Therefore, adult male Sprague–Dawley rats were orally given ML (10 and 20 mg/kg/day) 5 days before and after single CIS (5 mg/kg; i.p.) treatment. ML returned blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase that were elevated by CIS to normal level. The improved kidney function tests corroborated the attenuation of CIS renal injury at the microscopical level. It also reduced serum/renal nitric oxide and renal hemeoxygenase‐1. Meanwhile, ML hindered the raised levels of serum endothelin‐1, serum and renal tumor necrosis factor‐α, and monocyte chemoattractant protein‐1. These effects were associated by deceased caspase‐3 expression in kidney after ML treatment. In conclusion, ML guards against CIS‐induced nephrotoxicity via anti‐inflammatory and antiapoptotic properties.     

Precision-cut dog renal cortical slices in dynamic organ culture for the study of cisplatin nephrotoxicity

The dog is the non-rodent species the most often used in preclinical drug safety evaluation. In this study, we established a new system of precision-cut dog renal cortical slices, evaluated their biochemical, functional, and morphological integrity, and determined the effects of cisplatin (cis-diamminedichloroplatinum (II), CDDP), a very potent nephrotoxic antineoplastic agent used to treat a variety of solid tumors, on the viability and histopathology of slices. Precision-cut renal cortical slices were made perpendicular to the cortical-papillary axis. Slices were incubated in DMEM/Ham's F12 culture medium containing 1 g/L glucose, 2 mmol/L glutamine, and 2 mmol/L heptanoic acid at 37°C in an atmosphere of 5% CO₂-70% O₂-25% N₂ in dynamic organ culture. Our results showed that slices maintained ATP and GSH content, protein synthesis, Na⁺-dependent uptake of glucose inhibited by phlorizin, PAH (p-aminohippuric acid) uptake inhibited by probenecid, and TEA (tetraethylammonium) uptake inhibited by mepiperphenidol for at least 6 h of culture, and morphological integrity up to 24 h. After 6 h of exposure, CDDP induced vacuolation and cell necrosis in the epithelial tubular cells of slices with a concentration-related increase in extension but not in severity. The development of the lesions started in the proximal tubules and extended to the distal tubules. The location and the extension of the lesions confirmed the observations in dog kidneys after in vivo treatment with CDDP by the intravenous route. The concentration-related decrease in slice viability after 6 h exposure to CDDP was in keeping with the extension of the histopathological lesions in the renal parenchyma. The slice viability was unaffected up to 0.63 mmol/L CDDP. At 1.25 and 2.5 mmol/L CDDP, slice viability fell by 35% and 75%, respectively. These results suggest that precision-cut dog renal cortical slices in culture may be suitable for addressing the specific nephrotoxicity issues encountered in this species.Abbreviations CDDP cis-diamminedichloroplatinum (II) - FIS freshly isolated slices - GSH glutathione - GSSG glutathione disulfide - Hepes 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - MGP methyl--D-glucopyranoside - MTT 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide - PAH p-aminohippuric acid - PBS phosphate-buffered saline - TEA tetraethylammonium     

Response in shape and size of individual p31 cancer cells to cisplatin and ouabain: a computerized image analysis of cell halo characteristics during continuous perfusion

BACKGROUND: Volume regulation is essential for cellular functions, including cell death, such as apoptosis. Flow cytometry is standard for nonadherent cells, such as blood cells. Our aim was to explore image analysis methods to study adherent cancer cells of a solid tumor. METHODS: P31 mesothelioma cells were perifused (40 min) and studied by phase-contrast microscopy. A noise reduction of the cell contour was tested to more accurately yield the cell shape factor (SF). The optical halo around the cell was analyzed for information about membrane blebbing. RESULTS: The projected cell area (PCA) slowly increased under control perfusion, the halo outside more than the halo inside. Cisplatin (apoptosis) caused an immediate increase in the PCA-halo outside (5.9 +/- 1.2 %, P < 0.01, 1-5 min) and the SF indicated decreased roundness (P < 0.05). The SF-halo inside became more irregular than the outside, which was different from the control cells. The morphology reflected instant blebbing, and the cell bodies showed fragmentation after about 20 min. Ouabain resulted in only small changes in PCA and SF, significantly different from both control and cisplatin conditions. CONCLUSIONS: Image analysis (PCA and SF) on perifused adherent cancer cells may serve as a tool to follow the sensitivity of cancer chemotherapy and to study cell death patterns.     

Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats

Cisplatin has multiple cellular targets and modes of action that lead to nephrotoxicity. This suggests novel therapies that act at multiple cisplatin target sites may be effective. We tested whether human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can affect multiple target sites and protect against cisplatin-induced kidney damage. Rats were divided into four groups: control, infused with Ad-MSCs, injected with cisplatin, and cisplatin followed by infusion of Ad-MSCs. Animal survival and renal function were decreased and histological damage was increased in cisplatin-treated rats at day 3. Infusion of Ad-MSCs ameliorated renal dysfunction and tissue injury caused by cisplatin, leading to increased survival. Apoptotic cell death in the kidney was significantly reduced by infusion of Ad-MSCs. Activation of p53, JNK, and ERK and the expression of inflammation-related molecules were also decreased in the kidney that received Ad-MSCs. Very few Ad-MSCs were detected in the kidney. Conditioned medium from cultured Ad-MSCs had renal-protective functions in vivo and in vitro. Renal dysfunction and tissue damage caused by cisplatin were significantly reduced in rats treated with Ad-MSCs-conditioned medium. The viability of cultured renal proximal tubular cells exposed to cisplatin was also improved by coculture with Ad-MSCs or with conditioned medium. Release of proinflammatory mediators induced by cisplatin was inhibited in coculture with Ad-MSCs. Our results show that human Ad-MSCs exert a paracrine-protective effect on cisplatin nephrotoxicity at multiple target sites and suggest that human Ad-MSCs might be a new therapeutic approach for patients with acute kidney injury.     

Protective effect of Pongamia pinnata flowers against cisplatin and gentamicin induced nephrotoxicity in rats

Ethanolic extract of flowers of Pongamia pinnata was studied for its protective effect against cisplatin and gentamicin induced renal injury in rats. When the extract (300 & 600 mg kg(-1)) was administered orally for 10 days following cisplatin (5 mg kg(-1) i.p.) on day 5, toxicity of cisplatin, as measured by loss of body weight, elevated blood urea and serum creatinine declined significantly. Similarly in gentamicin (40 mg kg(-1) s.c.) induced renal injury, the extract (600 mg kg(-1)) normalized the raised blood urea and serum creatinine levels. Reversal of cisplatin and gentamicin renal cell damage as induced by tubular necrosis ie, marked congestion of the glomeruli with glomerular atrophy, degeneration of tubular epithelial cells with casts in the tubular lumen and infiltration of inflammatory cells in the interstitium was confirmed on histopathological examination. In the preventive regimen, co-administration of the extract with gentamicin significantly prevented the renal injury both functionally and histologically. Ethanolic extract of flowers had a marked nitric oxide free radical scavenging effect, suggesting an antioxidative property. Two flavonoids, known for their antioxidant activity viz. kaempferol and 3, 5, 6, 7, 8-pentamethoxy flavone were isolated from the extract. The results suggested that the flowers of Pongamia pinnata had a protective effect against cisplatin and gentamicin induced renal injury through antioxidant property.     

The synthesis,structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.     

Antitumor activity of Herceptin in combination with STEALTH liposomal cisplatin or nonliposomal cisplatin in a HER2 positive human breast cancer model

Single agent antitumor activity of Herceptin, a humanized monoclonal antibody directed against HER2, has been demonstrated in numerous preclinical and clinical studies. Additionally, combination therapy with Herceptin and chemotherapy (CRx) has demonstrated additive antitumor activity in both preclinical models and early clinical trials. STEALTH (pegylated) liposomal (PL) cisplatin, also known as SPI-077, is currently in clinical trials for a variety of solid tumors. The three studies reported here discuss the antitumor activity of the combination of Herceptin and nonliposomal cisplatin or PL-cisplatin in two xenograft tumor models, initiated from the cell lines, BT474 and MDA453, that overexpress the oncogene, HER2. Herceptin alone had significant antitumor activity in all three experiments (p < 0.0001). Nonliposomal cisplatin and PL-cisplatin were both effective antitumor agents but, at tolerable dose levels, PL-cisplatin was superior to nonliposomal cisplatin (p < 0.0003). The effect of combining Herceptin with the chemotherapeutic cisplatin or PL-cisplatin, was most significant at moderate doses of H (0.5 mg/kg, p < 0.0001), but tended to be greater than either agent alone in all experiments. The combination of PL-cisplatin with Herceptin had statistically similar antitumor activity to that of nonliposomal cisplatin with Herceptin in all experiments. We conclude that combination therapy with PL-cisplatin and Herceptin results in significant antitumor activity with the potential for reducing toxicity in metastatic breast cancer patients.     

Prevention: a real possibility to repress lung cancer

In the lack of effective treatment, the role of prevention has increased in the repressing of lung cancer. Smoking being a pathogenetic factor in the development of lung cancer is an accepted fact. Because of this, primer prevention means first of all the reduction of smoking both with the help of preventing smoking and cessation. A bigger - historical - debate has developed around secunder prevention: the effective screening of lung cancer. Although it was observed that staging rate and resecability had been more advantageous in the screened group, the screening of lung cancer was declared ineffective, because mortality did not improve. The change of approach can be felt from the middle of the 90's. Nowadays the creation of a multimodal lung cancer preventional strategy is in the center of researches. The screening of risk groups can mean the solution with the aid of biomarkers, chest X-ray and spiral CT. In Hungary, with the infrastructure of existing lung-screening network the up-to-date screening of risk groups seems to have reality in the near future.