Anthracycline antibiotics induce acute renal tubular toxicity in children with cancer

Bárdi, Edit; Bobok, I; Oláh, Anna V.; Kappelmayer, János; Kiss, Csongor

doi:10.1007/bf02893506

Cited by 39 publications

(18 citation statements)

References 15 publications

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“…Since all the animals were sacrificed on day-8, it is not known whether these animals would have survived if left alone beyond this timeframe with ongoing nephrotoxicity of this magnitude. Nevertheless, these observations may support the recommendation that patients on DOX should be monitored for Serum SUN and creatinine levels, prior to and following initial DOX dose either to rule out or address possible development of renal toxicity [61][62][63][64].…”

Section: Discussisonmentioning

confidence: 89%

“…In humans, approximately 50% of DOX is eliminated from the body unchanged [19] which gives ample opportunity for the parent molecule as well as its metabolites to interact with the kidneys [20]. Formation of a secondary alcohol, doxorubicinol, via a two-electron reduction of DOX is presumed to be the commonest biotransformation pathway [21].…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin-Induced In Vivo Nephrotoxicity Involves Oxidative Stress- Mediated Multiple Pro- and Anti-Apoptotic Signaling Pathways

Lahoti¹,

Patel²,

Thekkemadom³

et al. 2012

CNR

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Doxorubicin (DOX), a prominent anticancer agent has enjoyed considerable popularity in the last few decades because of its usefulness in the management of various forms of cancers, but its organotoxic potential (cardio-, hepatoand nephrotoxicity) has constrained on its clinical use. This study investigated whether DOX has the ability to cause nephrotoxicity in vivo and if so, whether it is linked to oxidative stress (OS). Another important goal was to describe whether expression of pro- and anti-apoptotic genes in kidneys was driven by OS. In order to explore DOX's nephrotoxic potential, male rats (Sprague Dawley; 500-520g; fed ad libitum) were administered i.p. with a single dose of DOX (12 mg/kg) on day one and sacrificed seven days later (day 8). Changes in serum chemistries (i.e., serum urea nitrogen, SUN, and creatinine) were determined immediately upon sacrifice, whereas kidney tissues were subjected to several sensitive biomarkers for OS, such as, lipid peroxidation, Superoxide dismutase (SOD) activity and chromatin fragmentation. The most important goal was to evaluate the select expression of Apaf-1, Caspase-3, Bad, Bax, Bcl-2, Bcl-xL, p53 and Mdm2 genes in order to understand the underlying link between extrinsic and intrinsic pathways of cell death. Data revealed that DOX-exposed animals showed significant nephrotoxicity as reflected in increased SUN (5.6-fold) and creatinine (2.65 fold) levels with considerably decreased body weight. Increases in kidney injury markers reflected parallel elevations in lipid peroxidation (1.7-fold) and genomic DNA fragmentation (2.9 fold) coupled with a proportionate reduction in total SOD activity suggesting DOX-assaulted kidneys encountered massive OS. Western blot showed very striking changes: i) substantial increases in the expression of pro-apoptotic APAF-1, Caspase-3, Bax and Bad proteins; ii) Reduction in the expression of anti-apoptotic Bcl-2 and Bcl-xL genes; iii) considerable increase in the expression of p53 and suppression of its regulator Mdm2. Serum chemistry and tissue biochemistry mirrored histopathology. In conclusion, this study for the first time may have shown a close link between mitochondrial perturbations and cell death regulating genes during DOXinduced nephrotoxicity, and described DOX's potential to inflict kidney injury in addition to other organs during chemotherapy in clinical setting.

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Section: Discussisonmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Doxorubicin-Induced In Vivo Nephrotoxicity Involves Oxidative Stress- Mediated Multiple Pro- and Anti-Apoptotic Signaling Pathways

Lahoti¹,

Patel²,

Thekkemadom³

et al. 2012

CNR

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“…Although our study shows that dexrazoxane reduces doxorubicin-associated cardiotoxicity without reducing oncological efficacy, another limitation is that we did not look at other possible cytoprotective activities, 69 such as reductions in nephrotoxicity, mitochondrial cardiotoxicity, neurotoxicity, and hepatotoxicity. 26,69,83–85 …”

Section: Discussionmentioning

confidence: 99%

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial

Lipshultz

Scully

Lipsitz

et al. 2010

The Lancet Oncology

394

302

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Summary Background Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. Methods Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. Findings 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: −0·82, 95% CI −1·31 to −0·33; end-systolic dimension: 0·57, 0·21–0·93) but not for those who also received dexrazoxane (−0·41, −0·88 to 0·06; 0·15, −0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46–0·48) and thickness-to-dimension ratio (0·66, 0·64–0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24–2·11), but not in boys (−0·10, −0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44–1·85), but not in boys (0·19, −0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3–12·1), event-free survival was 77% (95% CI 67–84) for children in the doxorubicin-alone group, and 76% (67–84) for children in the doxorubicin plus dexrazoxane group (p=0·99). Interpretation Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. Funding US Nat...

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“…3,4) However, increasing evidence shows that the antitumor agent also affects other organs including the liver, kidney and brain. 5,6) Almost 40% of patients suffered liver injury after doxorubicin treatment. 7) The main toxic effects on hepatocytes include: arrest cell cycle of hepatocytes, 8) oxidative stress and disruption of electron transport.…”

mentioning

confidence: 99%

Protective Effects of Berberine on Doxorubicin-Induced Hepatotoxicity in Mice

Zhao

Zhang

Tong

et al. 2012

Biological & Pharmaceutical Bulletin

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Doxorubicin, a very potent and often used anti-cancer drug, is largely limited due to the dose-related toxic effects. The present study investigated whether berberine, a natural product alkaloid, can reduce the liver injury induced by doxorubicin. Mice of either gender were randomly divided into four groups: the control group, doxorubicin group, berberine group, and berberine doxorubicin group. In the tests, body weight, general condition and mortality of the mice were observed, and serum alanine aminotransferase and aspartate transaminase levels were determined to evaluate liver function. Furthermore, the liver was excised for determination of the weight changes, as well as histopathological analysis in the tissues. Mortality rate and significant decline in body weight, and increased plasma alanine aminotransferase and aspartate transaminase activities were observed in doxorubicin-treated mice. These changes were significantly prevented by pretreatment with berberine. Histopathological studies showed that doxorubicin caused structural injuries, such as vascular congestion, inflammatory cell infiltration, hepatocellular degeneration and necrosis, fibrosis in the liver. These histopathological changes were largely attenuated by berberine pretreatment. These findings indicate that berberine has the hepatoprotective effect on doxorubicin-induced liver injury in mice.

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Anthracycline antibiotics induce acute renal tubular toxicity in children with cancer

Cited by 39 publications

References 15 publications

Doxorubicin-Induced In Vivo Nephrotoxicity Involves Oxidative Stress- Mediated Multiple Pro- and Anti-Apoptotic Signaling Pathways

Doxorubicin-Induced In Vivo Nephrotoxicity Involves Oxidative Stress- Mediated Multiple Pro- and Anti-Apoptotic Signaling Pathways

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial

Protective Effects of Berberine on Doxorubicin-Induced Hepatotoxicity in Mice

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