Although adriamycin (Doxorubicin) is one of the most effective and useful antineoplastic agents for the treatment of a variety of malignancies, its repeated administration can induce irreversible myocardial damage and resultant heart failure. Currently, no marker to detect early cardiac damage is available. The purpose of this study was to investigate whether an assessment of the acoustic properties of the myocardium could enable the earlier detection of myocardial damage after adriamycin chemotherapy. Forty Wistar rats were treated with adriamycin (2 mg/kg, i.v.) once a week for 2, 4, 6 or 8 weeks consecutively. Left ventricular ejection fraction (LVEF) was calculated using M-mode echocardiography data. The magnitude of cardiac cycle dependent variation of integrated backscatter (CVIB) of the myocardium was measured in the mid segment of the septum and in the posterior wall of the left ventricle, using a real time two dimensional integrated backscatter imaging system. LVEF was significantly lower in the adriamycin-treated 8-week group than in the controls (75 +/- 9 vs 57 +/- 8%, p < 0.05). Myocyte damage was only seen in the 8-week adriamycin-treated group. However, no significant changes of CVIB were observed between baseline or during follow-up in the ADR or control group. In conclusion, serial assessment of the acoustic properties of the myocardium may not be an optimal tool for the early detection of myocardial damage after doxorubicin chemotherapy in a rat model.
Animals ; Antibiotics, Antineoplastic/*toxicity ; Cardiomyopathies/*chemically induced/*ultrasonography ; Disease Models, Animal ; Doxorubicin/*toxicity ; *Echocardiography ; Male ; Rats ; Rats, Wistar ; Research Support, Non-U.S. Gov't

OBJECTIVEThe pathogenesis of minimal change nephrotic syndrome (MCNS) remains unclear. This study aimed to investigate the expression of interleukin-6 (IL-6) in rats with doxorubicin-induced nephropathy and its possible roles in the pathogenesis of MCNS.

METHODSEighty-three male Wistar rats were randomly assigned into a control group (n=32) and a nephropathy group (n=51). Nephropathy was induced by a single tail vein injection of doxorubicin (5 mg/kg). The control group was injected with normal saline. Twenty-four-hour urinary protein excretion was measured 7, 14, 28 and 42 days after doxorubicin injection. IL-6 expression in urine and renal tissues was determined using ELISA 7, 14, 28 and 42 days after doxorubicin injection.

RESULTSThe urinary protein excretion increased significantly in the nephropathy group 7, 14, 28 and 42 days after doxorubicin injection compared with that in the control group (P<0.01). IL-6 expression in urine and renal tissues increased significantly 7, 14, 28 and 42 days after doxorubicin injection compared with that in the control group (P<0.01). IL-6 expression in urine and renal tissues was positively correlated with 24-hour urinary protein excretion in the nephropathy group (r=0.794, P<0.01; r= 0.870, P<0.01). IL-6 expression in urine was positively correlated with that in renal tissues (r=0.739, P<0.01).

CONCLUSIONSIL-6 expression in the urine and renal tissues is increased in MCNS rats. IL-6 might play an important role in the pathogenesis of MCNS.

Animals ; Antibiotics, Antineoplastic ; toxicity ; Disease Models, Animal ; Doxorubicin ; toxicity ; Interleukin-6 ; analysis ; Kidney ; chemistry ; Male ; Nephrosis, Lipoid ; chemically induced ; immunology ; Rats ; Rats, Wistar

Animals ; Cardiomyopathies ; therapy ; Disease Models, Animal ; Doxorubicin ; toxicity ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; cytology ; Rabbits ; Transplantation, Autologous

PURPOSE: We have examined that dexamethasone inhibits apoptotic cell death of A549 lung epithelial cells through TRAIL and anti-cancer drugs. The purpose of the study is to determine the roles of GR, cIAP and NF- kappaB in this mechanism. MATERIALS AND METHODS: In the A549 lung epithelial cell line, TRAIL, taxol, doxorubicine & gemcitabine were used to investigate cell toxicity. Cells were pretreated 12 hours in advance with dexamethasone. RU486 was pretreated 30 minutes before dexamethasone. Crystal violet assay was used for cell toxicity tests. Apoptosis assay was performed by taking morphologic surveys with fluorescent microscopy after double staining with Hoechst 33342 & propium iodide. RT-PCR was used to investigate the gene expression of cIAP1 & cIAP2 by dexamethasone. Ad-IkappaBalpha-SR transduction study was used for the role of NF-kappaB. RESULTS: TRAIL and anti-cancer drug-induced apoptosis was partially suppressed in A549 cells pretreated with dexamethasone. The inhibitory effect on cell death disappeared in A549 cells pretreated with RU486. Using RT-PCR, changes of cIAP1 and cIAP2 genes manifestation in A549 cells subsequent to pretreatment with dexamethasone were examined. The results showed an increase in cIAP2 expression during a course of time which was suppressed by RU486 pretreatment. Induction of cIAP2 expression changes by dexamethasone was uniquely observed despite the blockade of NF-kappa by Ad-IkappaB alpha-SR transduction. CONCLUSIONS: These results suggest that dexametha sone inhibits TRAIL- and anti-cancer drug-induced apoptosis in A549 cells by inducing cIAP2 gene expression through a GR-mediated, NF-kappa-independent pathway.
Apoptosis ; Cell Death* ; Dexamethasone* ; Doxorubicin ; Epithelial Cells ; Gene Expression ; Gentian Violet ; Lung ; Microscopy ; Mifepristone ; NF-kappa B ; Paclitaxel ; Prednisone ; Toxicity Tests

The alkylating agent ifosfamide is an anti-neoplastic used to treat various pediatric and adult malignancies. Its potential urologic toxicities include glomerulopathy, tubulopathy and hemorrhagic cystitis. This report describes a case of proximal renal tubular dysfunction and hemorrhagic cystitis in a 67-year-old male given ifosfamide for epitheloid sarcoma. He was also receiving an oral hypoglycemic agent for type 2 diabetes mellitus and had a baseline glomerular filtration rate of 51.5 mL/min/1.73 m2. Despite mesna prophylaxis, the patient experienced dysuria and gross hematuria after a single course of ifosfamide plus adriamycin. The abrupt renal impairment and serum/urine electrolyte imbalances that ensued were consistent with Fanconi's syndrome. However, normal renal function and electrolyte status were restored within 14 days, simply through supportive measures. A score of 8 by Naranjo adverse drug reaction probability scale indicated these complications were most likely treatment-related, although they developed without known predisposing factors. The currently undefined role of diabetic nephropathy in adult ifosfamide nephrotoxicity merits future investigation.
Adult ; Aged ; Cystitis ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Doxorubicin ; Drug Toxicity ; Dysuria ; Fanconi Syndrome ; Glomerular Filtration Rate ; Hematuria ; Humans ; Ifosfamide ; Kidney Tubules, Proximal ; Male ; Mesna ; Sarcoma

To reveal the underlying mechanism of doxorubicin induced hepatotoxicity, an NMR-based metabolomic approach combined with multivariate statistical analysis was used to observe its metabolic alternations of rat liver. Sixteen differential metabolites between model rats and normal rats were characterized as potential pathological biomarkers related to doxorubicin induced hepatotoxicity. Six pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, and tyrosine metabolism were regarded as the targeted metabolic pathways according to Metabolic Pathway Analysis (MetPA). The results suggested that the metabolic perturbations in rats with doxorubicin induced hepatotoxicity were mainly involved in amino acid metabolism, lipid pathways, purine metabolism, energy metabolism, dysfunction of biotransformation and oxidative stress. The investigation revealed the effects of doxorubicin on liver in a holistic metabolic way, which laid a foundation for further studies on its toxicity mechanism.
Animals ; Biomarkers ; metabolism ; Doxorubicin ; toxicity ; Energy Metabolism ; Liver ; drug effects ; metabolism ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Metabolic Networks and Pathways ; Metabolomics ; Multivariate Analysis ; Oxidative Stress ; Rats

Animals ; Antibodies, Anti-Idiotypic ; therapeutic use ; Disease Models, Animal ; Doxorubicin ; toxicity ; Immunotherapy ; Interleukin-18 ; immunology ; pharmacology ; Male ; Mice ; Nephrosis, Lipoid ; chemically induced ; pathology ; therapy

In this paper, adriamycin-carboxymethyldextran magnetic nanoparticles (ADR-CMD MNPs) were prepared. After i.v. administration in mice, acute toxicity, cumulative toxicity and the distribution profiles of heart were studied both for free adriamycin(ADR) and ADR-CMD MNPs. The results showed conjugation with CMD MNPs, the acute toxicity of ADR was decreased significantly, the LD50 value of ADR-CMD MNPs was 5.06 times as high as that of the free ADR. Altogether, the cumulative toxicity of conjugate MNPs is significantly decreased as expressed by the mortality, the loss for both weight and leucocyte after repeated injection. Tissue distribution studies show the reduced cardiac uptake of ADR after i.v. which possibly contributes to minimizing the cardiotoxic effect of ADR.
Animals ; Dextrans ; Doxorubicin ; administration & dosage ; pharmacokinetics ; toxicity ; Drug Carriers ; Drug Delivery Systems ; Female ; Injections, Intravenous ; Magnetics ; Male ; Mice ; Myocardium ; metabolism ; Tissue Distribution

OBJECTIVETo explore the effect of Jianpi Qinghua Recipe (JQR) on renal functions of adriamycin-induced focal segmental glomerular sclerosis (FSGS) rats from the angle of activating fibroblasts to myofibroblast (MyoF).

METHODSTotally 56 rats were randomly divided into the normal control group (n=8), the sham-operation group (n =8), and the model group (n=40). The FSGS rat model was induced by nephrectomy of left kidney plus intravenous injection of adriamycin. Successfully modeled rats were further divided into 5 groups, i.e., the model group, the JQR group, the JPR (Jianpi Recipe) group, the QHR (Qinghua Recipe) group, and the NDQ (Niaoduqing) group, 8 in each group. Corresponding drugs were administered to rats in all groups, 2 mL each time, for 56 days. The effect of JQR on serum creatinine (SCr), urea nitrogen, 24-h urinary protein excretion, a-smooth muscle actin (alpha-SMA) mRNA, collagen type III (Col III) mRNA, fibronectin (FN) mRNA, and collagen type IV (Col IV) mRNA were observed.

RESULTSJQR could significantly lower SCr, urea nitrogen, and 24-h urinary protein excretion levels (P < 0.01), and significantly decrease mRNA levels of alpha-SMA, Col III, FN, and Col IV (P < 0.01). It was advantageous over the NDQ group. Compared with JPR, the relative expression levels of Col III mRNA and FN mRNA of JQR and QHR were significantly lower (P < 0.01).

CONCLUSIONSJQR could improve the renal function and renal fibrosis in the adriamycin-induced nephropathic model rats. Its efficacy was superior to that of NDQ. Its mechanisms might be linked with inhibiting activation of fibroblasts.

Animals ; Disease Models, Animal ; Doxorubicin ; toxicity ; Drugs, Chinese Herbal ; therapeutic use ; Fibrosis ; Kidney ; drug effects ; physiopathology ; Kidney Diseases ; chemically induced ; drug therapy ; physiopathology ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To explore the difference of mitochondrial DNA 4,834 bp deletion mutation in tissues of inner ear, kidney and skeletal muscle and to discuss the possible mechanism of this kind of mutation in doxorubicin induced mtDNA 4,834 bp deletion mutation rat model. METHOD: Twenty-eight Wistar rats were randomly divided into two groups, one was experimental group (18 rats), the other was the blank control group (10 rats). The rats of experimental group were treated with intraperitoneal injection doxorubicin (1 mg/kg) twice a week for 3 months. The blank controls received an equivalent volume of saline instead. The tissues of inner ear, kidney and skeletal muscle were harvested and the mitochondrial DNA 4,834 bp deletion mutation was detected by nested-PCR (nested polymers chain reaction) technique. The product of PCR was sequenced directly. RESULT: Two rats of the experimental group and the blank group died during the experiment. The frequency of the mitochondrial DNA 4,834 bp deletion mutation of inner ear, kidney and skeletal muscle were 68.75% (11/16), 75.00% (12/16) and 100.00% (16/16) respectively. The difference of this kind of mutation between tissues of the inner ear and the skeletal muscle was statistic significance (P < 0.05). There were no significant difference between the inner ear tissue and the kidney tissue (P > 0.05). None of the rats of the blank control group carry this kind of mitochondrial DNA mutation. CONCLUSION The mitochondrial DNA 4,834 bp deletion mutation could be induce by doxorubicin in rats, and a notable difference were found of the frequencies of this kind of mutation between tissues of the inner ear and the skeletal muscle. So it suggested that this kind of mitochondrial DNA common deletion mutation was tissue specific.
Animals ; DNA, Mitochondrial ; genetics ; Doxorubicin ; toxicity ; Ear, Inner ; Gene Deletion ; Kidney ; metabolism ; Muscle, Skeletal ; metabolism ; Rats ; Rats, Wistar ; Sequence Deletion ; drug effects