Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane

Purpose  The objective of the current investigation is to determine whether non-toxic doses of the catalytic topoisomerase-II inhibitor, dexrazoxane, have influence on the genomic damage induced by the anticancer topoisomerase-II poison, etoposide, on mice bone marrow cells. Method  The scoring of micronuclei, chromosomal aberrations, and mitotic activity were undertaken as markers of cyto- and genotoxicity. Oxidative damage markers such as reduced glutathione and lipid peroxidation were assessed as a possible mechanism underlying this amelioration. Results  Dexrazoxane pre-treatment significantly reduced the etoposide-induced micronuclei formation, chromosomal aberrations, and also the suppression of erythroblast proliferation in bone marrow cells of mice. These effects were dose dependent. Etoposide induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of etoposide challenge ameliorated these biochemical markers. Conclusion  Based on our data presented, strategies can be developed to decrease the etoposide-induced genomic damage in normal cells using dexrazoxane.     

右丙亚胺对阿霉素引起的心脏毒性防治效果及其机制研究

目的 探讨右丙亚胺对蒽环类药物(阿霉素)所致心脏毒性的防治效果及可能作用机制.方法 31只新西兰大白兔随机分为阿霉素[3 mg/(kg·week)×10,iv]组和阿霉素+右丙亚胺组[60 mg/(kg·week)×10,iv或ip],分别于用药前、用药第4周末及10周末测定血清超氧化物歧化酶(SOD)、丙二醛(MDA)、肌钙蛋白Ⅰ(cTnI)和脑钠肽(BNP)水平,超声心电图机检测心功能变化,并观察心肌组织病理形态学改变及心肌细胞凋亡情况.结果 阿霉素组实验前后对比,血清SOD活性降低,MDA含量升高(P＜0.05),cTnI和BNP浓度升高(P＜0.05),左室射血分数(LVEF)和左室短轴缩短率(LVFS)下降(P＜0.05);右丙亚胺可明显降低MDA、cTnI和BNP水平(P＜0.05),使LVEF和LVFS值升高(P＜0.05),并能减轻心肌病理损伤,减少心肌凋亡细胞.结论 右丙亚胺对阿霉素所引起的心脏毒性具有一定的保护作用,其作用机制主要是减少氧自由基的产生、降低脂质过氧化产物含量和减轻心肌细胞凋亡.     

Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats

Purpose: To compare the protective effects of amifostine and dexrazoxane against the chronic toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR). Methods: The animals were pretreated with amifostine (200 mg/kg, i.p.), dexrazoxane (25 mg/kg, i.p.) or saline 30 min before the administration of doxorubicin (1 mg/kg, i.v.), once-weekly for 12 weeks. Control animals received similar amounts of amifostine or saline. The SHR underwent necropsy examination 1 week after the last dosing, and cardiac, renal, and gastrointestinal lesions were graded semiquantitatively. Results: Amifostine and dexrazoxane provided equal degrees of protection against the renal toxicity of doxorubicin. However, dexrazoxane was more cardioprotective than amifostine, and prevented the mortality induced by doxorubicin. This mortality was not decreased by pretreatment with amifostine. The loss of body weight caused by doxorubicin was actually worsened by coadministration of amifostine. Conclusions: Compared to dexrazoxane, amifostine provided a comparable degree of protection against the nephrotoxicity of doxorubicin, but was less cardioprotective and did not prevent the mortality and loss of body weight produced by doxorubicin. These differences may be related to the fact that amifostine may act as a scavenger of reactive oxygen species, whereas dexrazoxane may prevent their formation. Received: 20 May 1999 / Accepted: 14 October 1999     

Overview,prevention and management of chemotherapy extravasation

Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.     

阿霉素对斑马鱼心脏毒性的评估及机制探索

目的 :通过观测阿霉素致斑马鱼胚胎产生心脏毒性的表型,及联用右丙亚胺保护剂,建立实验室心脏毒性药物评价及研究的模型。方法:选择受精后24 h的AB系野生型斑马鱼胚胎,分别暴露于不同浓度的阿霉素中后,选择心脏毒性表型最明显的阿霉素浓度,将其分别联用或不联用右丙亚胺作用48 h。在斑马鱼胚胎发育至受精后72 h时,在显微镜下观察其心血管系统的形态学改变,记录心率变化,并分别抽提斑马鱼胚胎RNA,检测心脏发育相关基因及氧化、抗氧化相关指标。结果:随着阿霉素浓度的升高,斑马鱼出现了如胚胎发育畸形、心包水肿等改变,且死亡率升高,心脏毒性表型最明显的阿霉素浓度为64.40μmol/L,而联用右丙亚胺(130.47μmol/L、260.93μmol/L)则可有效挽救阿霉素对斑马鱼心脏的毒性作用,并可分别将其胚胎生存率由35%显著提升至90%和88.3%(P<0.001),而右丙亚胺可有效清除丙二醛并恢复SOD活性。结论:成功建立了斑马鱼评价心脏毒药物的模型。阿霉素对斑马鱼胚胎的心脏毒性呈浓度依赖性增加,且与斑马鱼胚胎死亡率亦呈正相关,而右丙亚胺则可有效挽救阿霉素致斑马鱼胚胎的心脏毒性,并降低其死亡率,且此作用与斑马鱼心脏发育相关基因无关,但与氧化及抗氧化通路有明显的相关性。     

Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy

Management of anthracycline extravasation is problematic and most reports are anecdotal. On September 6, 2007, the U.S. Food and Drug Administration approved Totect 500 mg (dexrazoxane hydrochloride for injection) for the treatment of extravasation resulting from i.v. anthracycline chemotherapy. In two studies, a total of 57 evaluable patients experienced extravasation from peripheral vein or central venous access sites with local swelling, pain, or redness. The presence of anthracycline in skin biopsy tissue was confirmed by tissue fluorescence, and treatment with a 3-day schedule of dexrazoxane began within 6 hours of the event. The primary endpoint was a reduction in the need for surgical intervention. Only one patient required surgical repair of the injury site, and late sequelae in the remainder were absent or mild. Also, the sponsor, TopoTarget A/S, Copenhagen, Denmark, performed controlled nonclinical studies in support of dexrazoxane dose and timing for the reduction of tissue injury resulting from anthracycline extravasation. For this uncommon but serious complication of anthracycline therapy, the need for surgical intervention was 1.7% with this regimen.     

Gender-Dependent Reductions in Vertebrae Length, Bone Mineral Density and Content by Doxorubicin Are Not Reduced by Dexrazoxane in Young Rats: Effect on Growth Plate and Intervertebral Discs

Doxorubicin (DOX) is widely used in anti-cancer cocktails. Dexrazoxane (DXR) is a cardioprotectant approved for use with DOX. The effect of DOX, with or without DXR, on bone in children is not well understood. The aim of this study was to examine the effect of DOX on vertebrae and femur length and bone density acquisition in young rats, as well as to test the hypothesis that young females are more susceptible to DOX-induced tissue damage than young males. The results of this study suggest that a single injection of DOX in young female and not male rats is associated with low bone turnover resulting in vertebrae and femur bone growth deficits. DOX selectively decreased BMD and BMC accrual in the lumbar verterbrae that was not prevented by DXR. DOX-treated rats also exhibited growth plate and intervertebral disc defects. This information will be useful in the design of interventions to promote bone growth or retard bone loss during DOX treatment.     

Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies

Purpose Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion.Methods Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m² and doxorubicin 165 mg/m², and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 g/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 l^–1. Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations.Results Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (<500 l^–1) was nine and of platelet count <20,000 l^–1 was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM.Conclusions These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.     

Cytoprotection: concepts and challenges

Clinical trials with several toxicity protectors (cytoprotective or chemoprotective agents) have been performed during the past decade. These trials are quite complex since they must include sufficient dose-limiting events for study, and assessment of both toxicity (and therefore the efficacy of protection) and antitumor effects must be carried out. However, it is inevitable that with greater understanding of drug actions, one seeks to manipulate these for greater antitumor activity (biochemical modulation) or for lesser dose-limiting toxicity (cytoprotection) or for both. Examples of cytoprotective agents include dexrazoxane (ICRF-187), protecting against doxorubicin cardiotoxicity, and amifostine protecting against the myelosuppression of platinum and alkylating agents. In spite of the challenges encountered in the clinical development of these drugs, studies of cytoprotectors have led to a considerable understanding of important therapeutic issues and tangible clinical benefit in specific clinical situations.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8±83.4 mg/m² in the dexrazoxane group and 266.1±75.0 mg/m² in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.