Toxicity, outcome, and management of anthracycline overdoses in 16 dogs.

BACKGROUND: Despite multiple reports of chemotherapy overdoses (ODs) in human and veterinary medicine, anthracycline ODs have been described infrequently. HYPOTHESIS/OBJECTIVES: Describe toxicities, treatments, and overall outcome after anthracycline OD in dogs. ANIMALS: Twelve mitoxantrone (MTX) and 4 doxorubicin (DOX) ODs were evaluated. METHODS: Multicenter retrospective analysis. The American College of Veterinary Internal Medicine oncology and internal medicine listservs were solicited for cases in which a chemotherapy OD occurred. RESULTS: Sixteen anthracycline cases were collected. Anthracycline ODs occurred because of an error in chemotherapy preparation (n = 9), or dose miscalculation (n = 7). The overall median OD was 1.9× (range, 1.4-10×) the prescribed amount. Most ODs were identified immediately after drug administration (n = 11), and the majority of patients were hospitalized on supportive care (n = 11) for an average of 8 days (range, 3-34 days). Adverse events after the OD included neutropenia (94%), thrombocytopenia (88%), anemia (63%), diarrhea (63%), anorexia (56%), vomiting (38%), lethargy (31%), and nausea (25%). Two patients did not survive the OD. High grade neutropenia was common and did not appear to be mitigated by the administration of filgrastim. CONCLUSIONS AND CLINICAL IMPORTANCE: All patients received supportive care after identifying the OD and death was uncommon. Further evaluation is needed to determine ideal therapeutic guidelines anthracycline OD.

Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy.

Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.

Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart.

The clinical use of doxorubicin (DOX) is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether voluntary exercise training would confer protection against DOX cardiotoxicity in the isolated perfused rat heart. Female Sprague-Dawley rats were randomly assigned to standard holding cages or cages with running wheels for 8 wk. Twenty-four hours after the sedentary (SED) or voluntary exercise (VEX) running period, rats were anesthetized with pentobarbital sodium, and hearts were isolated and perfused with oxygenated Krebs-Henseleit (KH) buffer at a constant flow of 15 ml/min. After a 20-min stabilization period, hearts were paced at 300 beats per minute and perfused with KH buffer containing 10 microM DOX for 60 min. A set of control hearts from SED and VEX rats were perfused under identical conditions without DOX for the same period. DOX perfusion led to significant decreases in left ventricular developed pressure, +dP/dt, and -dP/dt, and significant increases in LV lipid peroxidation in sedentary rats compared with non-DOX controls (P < 0.05). Prior voluntary exercise training attenuated these DOX-induced effects and was associated with a significant increase (78%, P < 0.05) in heat shock protein (HSP72), but not mitochondrial isoform of SOD (MnSOD) or CuZnSOD protein expression in the hearts of wheel-run animals. These data indicate that chronic physical activity may provide resistance against the cardiac dysfunction and oxidative damage associated with DOX exposure and provide novel evidence of HSP72 induction in the heart after voluntary exercise.

[Air embolus as a complication of a haemoperfusion catheter removal after iatrogenic intoxication with doxorubicin--a case report]. / Zator powietrzny jako powiklanie usuniecia cewnika do hemoperfuzji po jatrogennym zatruciu doksorubicyna--opis przypadku.

UNLABELLED: The case of a 67-year-old patient, treated for melanoma, who was given a toxic dose of doxorubicin (600 mg/m2), was described. The haemoperfusion was performed a short time after intoxication. No toxic effects were seen during the observation for three weeks. The catheter was removed from the sitting patient by an oncologist. The patient abruptly lost consciousness, there were also cyanosis, loss of muscle tone and apnea. The reanimation was unsuccessful. The air embolism was probably the cause of death. The diagnosis was confirmed by the sudden attack, wide duct after the removal of catheter, sitting position of the patient and the presence of foramen ovale found during autopsy. CONCLUSIONS: Cannulation as well as decannulation of the central vessels should be performed by experienced doctors. Decannulation should always be done in the Trendelenburg position.

Toxicidad por sobredosis de mitomicina / Toxicity of mitomycin-C overdose

La toxicidad hematológica de la mitomicina C es tardía y puede aparecer meses después de la administración del fármaco. Es excepcional encontrar casos de toxicidad por sobredosis de mitomicina. Presentamos un caso de aplasia medular severa y prolongada tras sobredosificación de mitomicina-C. La dosis total acumulada (100 mg/m2) fue prácticamente el doble de la que se recomienda habitualmente y se administró con una pauta semanal a lo largo de cinco semanas. El paciente ingresó tres meses después de la primera dosis con deterioro del estado general, aplasia medular confirmada mediante biopsia y ascitis secundaria a recidiva abdominal de adenocarcinoma gástrico. La toxicidad hematológica se mantuvo durante los 69 días que duró el ingreso y no comenzó a recuperarse hasta casi cinco meses después de la primera dosis de mitomicina (AU)

Cardiotoxic transplacental effect of idarubicin administered during the second trimester of pregnancy.

Polychemotherapy including idarubicin was administered during the second trimester to treat acute lymphoblastic leukemia. The infant delivered at 28 weeks' gestation had acute cardiac failure attributed to the cardiotoxic effect of idarubicin. Cardiotoxicity may be caused by idarubicin's biophysical properties that facilitate its transplacental passage. Idarubicin should be used with extreme caution during pregnancy.

Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction.

The role of iron in anthracycline toxicity was studied in rats in vivo in intact animals and in vitro in heart cell cultures. In animals treated with 8 mg/kg doxorubicin, iron loading resulted in severe weight loss and a twofold increase in rate of mortality. Studies in cultured heart cells aimed at defining the subcellular target of interaction between iron and anthracycline toxicity showed no evidence of anthracycline-induced damage to sarcolemmal thiolic enzymes represented by 5'-nucleotidase and only a limited increase in lysosomal fragility as monitored by an increase in beta-hexosaminidase activity in cell homogenates and its release into the culture medium. By contrast, doxorubicin treatment resulted in a marked inhibition of mitochondrial function as monitored by a decrease in carbon 14-labeled palmitate utilization, to 33% +/- 4% of controls, and prior iron loading resulted in a further decrease in palmitate utilization, to 18% +/- 3% of controls. Conversely, iron-chelation treatment by either deferoxamine or deferiprone (L1) eliminated the harmful effects of iron loading and resulted in a partial inhibition of doxorubicin toxicity in both normal and iron-loaded cells. Our studies represent the first demonstration in intact animals of the potentiation of anthracycline toxicity by iron overload. They also indicate that mitochondria represent an important target of combined iron-anthracycline toxicity. These observations provide new insights into the mechanism of anthracycline cardiotoxicity and may be useful in developing better strategies for tumor therapy.

The predictive value of myocardial radioisotope scanning in animals treated with doxorubicin.

Thirty-four New Zealand white rabbits were treated with doxorubicin and imaged weekly with Tc-99m pyrophosphate to define the value of abnormal myocardial images in predicting doxorubicin-induced cardiac toxicity. Increased myocardial uptake was detected in most animals on sustained treatment with doxorubicin. A greater proportion of the heart was involved with doxorubicin-related histologic changes in animals with strongly positive myocardial images than in treated animals with moderately positive or normal scans. The myocardial images returned to normal levels 2--6 wk after doxorubicin was discontinued. Five of seven rabbits that received doxorubicin after they had three moderately positive myocardial scans, died from congestive heart failure. Three rabbits whose doxorubicin was discontinued because of scan findings, survived for 6 wk or more before dying from renal failure. The three rabbits who received the highest total dose of doxorubicin died of renal failure without developing abnormal myocardial scans.