Iron chelator; cardioprotective agent

体外活性：右雷佐生 (10 mM) 临床上已知可限制蒽环类药物的心脏毒性，可防止柔红霉素诱导的心肌细胞凋亡，但不能防止大鼠心肌细胞中较高蒽环类药物浓度诱导的坏死。右雷佐生可能通过结合游离或松散结合的铁，或与多柔比星络合的铁来发挥其心脏保护作用，从而防止或减少损害细胞成分的位点特异性氧自由基的产生。 Dexrazoxane 特异性消除 H9C2 心肌细胞中阿霉素（而非喜树碱或过氧化氢）诱导的 DNA 损伤信号 γ-H2AX。 Dexrazoxane 还会诱导 Top2beta 快速降解，这与多柔比星诱导的 DNA 损伤的减少是平行的。 Dexrazoxane 通过干扰 Top2beta 来拮抗阿霉素诱导的 DNA 损伤，这可能表明 Top2beta 与阿霉素心脏毒性有关。右雷佐生在细胞内水解为其活性形式，并与铁结合以防止超羟基自由基的形成，从而防止线粒体破坏。

右雷佐生与多柔比星、柔红霉素或伊达比星联合使用，可使 B6D2F1 小鼠的组织损伤（以伤口大小乘以持续时间的曲线下面积表示）分别减少 96%、70% 和 87%。右雷佐生与多柔比星、柔红霉素或伊达比星联合使用，可显着减少小鼠伤口的比例以及伤口的持续时间。

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利用多种化学疗法治疗癌症的进展显著提高了癌症的生存率。接受多柔比星（DXR）化疗的癌症女性幸存者通常会出现卵巢功能急性受损，这种情况可能会持续长期、永久性卵巢功能不全。Dexrazoxane（Dexra）预处理可减少DXR诱导的心脏损伤，并保护体外培养的小鼠和非人灵长类动物卵巢，证明了一种基于药物的屏障可以防止DXR损伤。本研究测试了Dexra预处理在治疗后的前24小时内减轻小鼠急性DXR化疗卵巢毒性的能力，并在整个生殖期内改善随后的长期生育能力。在DXR治疗前1小时，以1:1 mg或10:1 mg Dexra:DXR的比例用Dexra治疗青春期CD-1小鼠。在急性损伤期（注射后2-24小时），以1:1 mg的比例进行Dexra预处理可减少双链DNA断裂的程度，减少γH2FAX的激活，并减少DXR引起的随后卵泡细胞死亡。在生育能力和繁殖力研究中，用Dexra:DXR剂量比预处理的母鼠的产仔数大于用DXR治疗的母鼠，用1:1 mg Dexra:DXR剂量比治疗的小鼠产下的幼崽出生体重大于用DXR治疗的雌性。虽然DXR在治疗后的6次妊娠中显著提高了“不孕指数”（量化未能怀孕的母鼠百分比），但Dexra预处理显著降低了DXR治疗后的不孕指数，提高了繁殖力。低剂量地塞米松不仅保护了卵巢，而且在暴露于DXR化疗后也具有相当大的生存优势。小鼠存活率从DXR治疗后的25%增加到Dexra治疗前的80%以上。这些数据表明，Dexra对DXR毒性提供了急性卵巢保护，改善了小鼠模型的生殖健康，表明这种临床可用的药物可能为癌症患者提供卵巢保护[3]。

细胞用0.1%DMSO（溶剂对照）或200μmol/L的Dexrazoxane处理5小时，然后与阿霉素共孵育1天或VP-16共孵育2天。然后向每个孔中加入MTT（0.1mg），并在37°C下再孵育细胞4小时。去除培养基后，加入DMSO，使用微孔板读数器测量570nm处的吸光度。平均IC50值（平均值±SE）分为三份或四份。[1]

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Neutral comet assay。原代MEF在37°C的CO2培养箱中用DMSO或阿霉素处理1.5小时，然后在新鲜培养基中再培养30分钟，以逆转Top2切割复合物。H9C2细胞用DMSO或Dexrazoxane（100μmol/L）处理3小时，洗涤并补充新鲜培养基。然后用DMSO或阿霉素处理细胞1.5小时，然后在新鲜培养基中再孵育30分钟，以逆转Top2切割复合物。然后洗涤细胞，用0.005%胰蛋白酶胰蛋白酶消化，并重新悬浮在补充有10%FetalPlex动物血清复合物（10000/mL）的DMEM中。然后在37°C下将细胞悬浮液（50μL）与500μL 0.5%低熔点琼脂糖混合。将细胞/琼脂糖混合物（75μL）转移到载玻片上。然后将载玻片浸入预冷的裂解缓冲液[2.5 mol/L NaCl、100 mmol/L EDTA、10 mmol/L Tris（pH 10.0）、1%Triton X-100、10%DMSO]中1小时，然后在1×Tris-硼酸盐-EDTA（TBE）缓冲液中平衡30分钟。载玻片在1.0 V/cm的1×TBE中电泳10分钟，并用Vistra Green 染色。图像在荧光显微镜下可视化，并用电荷耦合器件相机捕获。如前所述，通过测量每个治疗组的至少100个细胞来确定平均彗尾矩。使用Student t检验对平均彗尾矩进行了统计分析。[1]

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Band depletion assay。H9C2细胞（1.2×105）在存在或不存在Dexrazoxane（150μmol/L）的情况下用250μmol/L VP-16处理15分钟。细胞要么立即裂解，要么在裂解前在37°C的无药物培养基中再孵育30分钟（以逆转Top2裂解复合物）。使用抗Top2α/Top2β和抗α-微管蛋白抗体通过蛋白质印迹分析细胞裂解物。Top2切割复合物的量可以通过逆转后游离Top2的量与未逆转的游离Top2量之间的差异来估算[1]。

Mice [3]
All surgery was performed under Ketamine and isofluorane anesthesia. Female CD-1 mice were allowed to acclimate to the laboratory environment for one week prior to the start of an experiment under the supervision and care of the animal facility staff. At 4 weeks of age, the adolescent mice were injected with Dexrazoxane/Dexra or vehicle control (0.0167 M lactate in saline) via intraperitoneal injection using ≤ 200 μL/injection 1 hour prior to DXR injection. DXR or vehicle (saline) was subsequently administered via intraperitoneal injection.

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Acute treatment [3]
At 4 weeks of age, mice were treated with 1) Vehicle for Dexrazoxane/Dexra + Vehicle for DXR, 2) Vehicle for Dexra + 20 mg/kg DXR, 3) 20 mg/kg Dexra + Vehicle for DXR, or 4) 20 mg/kg Dexra + 20 mg/kg DXR; doses were calculated based on the average weight of a 4-week-old CD-1 mouse. The 20 mg/kg DXR dose represents twice the maximum human equivalent DXR dose and was chosen in order to engage ample acute DXR toxicity. The 20 mg/kg Dexra dose represents a 1:1 Dexra/DXR mg ratio, providing a significant dose reduction from that used in cardioprotection to limit potential side effects of Dexra. The chosen Dexra dose was based on our previous in vitro study demonstrating a 2 μM Dexra dose, 100-folds lower than that used in in vitro cardiac protection studies, preserved granulosa cell viability against DXR. Animals were euthanized with CO2 followed by cervical dislocation and ovaries removed surgically 0, 2, 4, 10, 12 or 24 h after the second injection. Experiments were carried out in 4 biological replicates in which 3 mice were treated per drug group and harvested for each time point per biological replicate; in sum, n = 12 animals per treatment were totaled across all replicates. Ovaries were placed in 2 mL phosphate buffered saline, pH 7.4, and cleared of fat and attached bursa. For each ovarian pair, one was fixed in 10% formalin and processed for TUNEL assay, and the second was processed for a neutral comet assay. Separate mice were treated to provide ovaries utilized for protein extraction followed by Western blot analysis as previously described.

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Breeding trial [3]
Female CD-1 mice were housed in Innovive system cages from 3 weeks until 8 months of age. At 4 weeks of age, mice were treated with: 1) Vehicle for Dexrazoxane/Dexra + Vehicle for DXR, 2) Vehicle for Dexra + 10mg/kg DXR, 3) 10mg/kg Dexra (1:1 mg ratio) + 10mg/kg DXR, 4) 100 mg/kg Dexra (10:1 mg ratio) + 10mg/kg DXR, 5) 10mg/kg Dexra (1:1 mg ratio) + Vehicle for DXR, or 6) 100mg/kg Dexra (10:1 mg ratio) + Vehicle for DXR. DXR was administered at 10 mg/kg body weight (a human equivalent dose of 30mg/m2) to minimize long-term cardiotoxicity. Dexra dose is expressed as a ratio to DXR dose throughout the manuscript. Dexra was administered at either a 1:1 mg ratio (labeled as Dexra1:DXR1, groups 3 above) or 10:1 mg ratio (labeled as Dexra10:DXR1, group 4 above, currently used in cardioprotective protocols) to DXR as indicated. Dexra control-treated animals (groups 5 and 6, above) are labeled as DexraC (DexraC1 and DexraC10 respectively) throughout the manuscript. At 6 weeks of age and prior to breeding, animals were treated for two weeks with drinking water medicated with enrofloxacin (22.7 mg/ml) at a calculated dose of 5 mg/kg (0.5 mL/300 mL ddH2O bottle) as a prophylactic to mitigate the side effects of a compromised immune system brought on by DXR treatment. At 8 weeks of age, females were moved to breeder cages where two females were paired with one male. Females were continuously mated from 8 weeks of age to 8 months of age or until 6 litters were achieved. Males were rotated following each breeding round to minimize any potential male-specific infertility effect. Animals within the breeder cage were fed a maintenance chow diet with protein: 24%; Fat: 4%; Fiber: 4.5% as well as irradiated sunflower seeds. Bi-weekly assessment of animal health was conducted, and additional nutritive support via DietGel® and sunflower seeds was given to females having difficulty maintaining body condition. Females remained within the breeder cage until they showed visual or palpable signs of pregnancy, at which point they were separated and maintained on a breeder irradiated diet (Protein: 19%; Fat: 9%; Fiber: 5%) until parturition. The health of the breeding mice was monitored at least three times daily when the mice were near parturition. [3]
br> Following delivery, pups were separated and the females were returned to the breeder cage within 24 h post-partum. The pups were counted, weighed, and euthanized on post-natal day 1 (PND1). At 8 months of age, the now non-pregnant dams were weighed, anesthetized with isoflurane (confirmed with limb pinch) and sacrificed via terminal blood draw followed by cervical dislocation. A terminal blood draw was carried out for future studies. Ovaries were removed from each female and weighed. Mice that did not survive to breeding age or that displayed signs of deteriorating health were removed from the breeding trial to minimize any suffering. The breeding trial was carried out in 4 replicates, with 3–6 mice per group per replicate, where the total number of female mice in each group at the start of breeding was 16 control, 16 DXR, 21 Dexrazoxane/Dexra1:DXR1, 16 Dexra10:DXR1, 12 DexraC1, and 12 DexraC10 across all 4 replicates. Data for survival analysis, pup weights, and litter sizes were included for analysis at the intervals for which the dam was present in the trial. Infertility index was conducted on mice that gave birth at each mating round and ovarian weight analysis was conducted at 8 months.

Absorption, Distribution and Excretion
IV administration results in complete bioavailability.
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.
9 to 22.6 L/m^2
7.88 L/h/m2 [dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane]
6.25 L/h/m2 [dose of 60 mg/m2 Doxorubicin and 600 mg/m2 Dexrazoxane]
After intravenous administration, the drug is rapidly distributed into tissue fluids, the highest concentrations of the parent drug and its hydrolysis product being found in hepatic and renal tissues.
The mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL at the end of the 15-minute infusion of a 500 mg/sq m doxorubicin dose. Following a rapid distributive phase, dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours.
The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/sq m ).
In vitro studies have shown that /dexrazoxane/ is not bound to plasma proteins.
For more Absorption, Distribution and Excretion (Complete) data for DEXRAZOXANE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.
Metabolic products include the unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products of unknown concentrations.
In vitro studies have shown dexrazoxane to be hydrolysed by DHPase in liver and kidney, but not heart extracts.
/This/ study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide. Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay. The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 hr. A plasma concentration of 10 micro M ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 micro M ADR-925 was maintained for 4 hr and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses. The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.
Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.
Route of Elimination: Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.
Half Life: 2.5 hours

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Biological Half-Life
2.5 hours
The distribution half-life has ranged from about 12 to 60 minutes ...
Elimination - 2.5 hours.

Toxicity Summary
The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane (a prodrug) is converted intracellularly to a ring-opened bidentate chelating agent that chelates to free iron and interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. It should be noted that dexrazoxane may also be protective through its inhibitory effect on topoisomerase II.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of dexrazoxane during breastfeeding. The manufacturer recommends that women not breastfeed during treatment and for 2 weeks following the final dose of dexrazoxane. However, because dexrazoxane is used with doxorubicin, the abstinence period might be longer, depending on the doxorubicin dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Very low (< 2%)

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Toxicity Data
Man(iv): TDLo: 383 mg/kg
Mouse(ip): LDLo 800 mg/kg
Dog(iv): LDLo: 2 gm/kg
Intraperitoneal, mouse LD₁₀ = 500 mg/kg. Intravenous, dog LD₁₀ = 2 gm/kg.

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Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/sq m ) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/sq m ) in a crossover study in cancer patients.

[1]. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007 Sep 15;67(18):8839-46.

[2]. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circ Res. 1999 Feb 19;84(3):257-65.

[3]. Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice. PLoS One . 2015 Nov 6;10(11):e0142588.

(+)-dexrazoxane is a razoxane. It has a role as a chelator, an antineoplastic agent, a cardiovascular drug and an immunosuppressive agent.
Dexrazoxane is a Cytoprotective Agent.
Dexrazoxane is a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities. After hydrolysis to an active form that is similar to ethylenediaminetetraacetic acid (EDTA), dexrazoxane chelates iron, limiting the formation of free radical-generating anthracycline-iron complexes, which may minimize anthracycline-iron complex-mediated oxidative damage to cardiac and soft tissues. This agent also inhibits the catalytic activity of topoisomerase II, which may result in tumor cell growth inhibition.
An antimitotic agent with immunosuppressive properties. Dexrazoxane, the (+)-enantiomorph of razoxane, provides cardioprotection against anthracycline toxicity. It appears to inhibit formation of a toxic iron-anthracycline complex. The Food and Drug Administration has designated dexrazoxane as an orphan drug for use in the prevention or reduction in the incidence and severity of anthracycline-induced cardiomyopathy.
The (+)-enantiomorph of razoxane.
See also: Dexrazoxane Hydrochloride (has salt form).

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Drug Indication
For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m^2 and would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation from intravenous anthracyclines.
FDA Label
Savene is indicated for the treatment of anthracycline extravasation.

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Mechanism of Action
The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane (a prodrug) is converted intracellularly to a ring-opened bidentate chelating agent that chelates to free iron and interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. It should be noted that dexrazoxane may also be protective through its inhibitory effect on topoisomerase II.
The mechanism of action of dexrazoxane's cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of ethylenediamine tetra-acetic acid (EDTA) that readily penetrates cell membranes. Laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.

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Therapeutic Uses
Cardioprotectant
Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with the administration of doxorubicin in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/sq m of body surface and who would benefit from continued therapy with doxorubicin. /Included in US product labeling/
/Exptl Ther:/ Accidental extravasation of chemotherapy containing anthracycline often causes mutilating complications as a result of extensive tissue necrosis. Treatment therefore consists of extensive surgical debridement. We present the case of a 41-year-old woman with breast cancer who experienced extravasation of epirubicin. She was treated with an intravenous infusion of dexrazoxane for three successive days and recovered without surgical treatment and only slightly dysaesthesia in the surrounding tissue. Although infusion of dexrazoxane for this indication is still experimental we consider it a promising treatment for patients who have accidental extravasation of anthracyclines.

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Drug Warnings
Dexrazoxane is not indicated for use at the time of initiation of doxorubicin therapy. Cconcurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy is not recommended because of possible interference with the antitumor efficacy of the regimen.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Dexrazoxane may add to the myelosuppression caused by chemotherapeutic agents.
Do not use with chemotherapy regimens that do not contain anthracycline.
For more Drug Warnings (Complete) data for DEXRAZOXANE (8 total), please visit the HSDB record page.

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Pharmacodynamics
Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose. Patients receiving anthracycline-derivative antineoplastic agents may experience three types of cardiotoxicity: acute transient type; chronic, subacute type (related to cumulative dose and has a more indolent onset later on); and a late-onset type that manifests years after therapy, mainly in patients that have been exposed to the drug as a child. Although the exact mechanism of anthracycline-induced cardiotoxicity is not known, it has shown to exert a variety of actions that may result in the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase. This may lead to myofibrillar loss associated with anthracycline-induced cardiotoxicity. Anthracyclines may also cause myocyte damage via calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Furthermore, it has been suggested that the main cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA. The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines also contain a quinone structure that can undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals. This complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals. The toxicity induced by antrhacyclines may be exacerbated in cardiac cells, as these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage.

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Dexrazoxane Hydrochloride is the hydrochloride salt of a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities. After hydrolysis to an active form that is similar to ethylenediaminetetraacetic acid (EDTA), dexrazoxane chelates iron, limiting the formation of free radical-generating anthracycline-iron complexes, which may minimize anthracycline-iron complex-mediated oxidative damage to cardiac and soft tissues. This agent also inhibits the catalytic activity of topoisomerase II, which may result in tumor cell growth inhibition.
The (+)-enantiomorph of razoxane.
See also: Dexrazoxane (has active moiety).

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Drug Indication
Savene is indicated for the treatment of anthracycline extravasation.

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Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks. [1]

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The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis. In contrast, dexrazoxane (10 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to limit the toxicity of these drugs.[2]

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Dexrazoxane/Dexra mitigated acute DXR-induced ovarian toxicity and improved the fertility window as shown by increased fecundity, pup weight, litters size, and number of deliveries post-DXR therapy. The 1:1 Dexra:DXR dose conferred ovarian protection. Easy-to-administer Dexra may provide a timely, cost effective and safe, drug-based method for ovarian protection, particularly for prepubertal and adolescent girls for whom oocyte and embryo freezing are not viable fertility preservation options.[3]

C11H16N4O4

268.27

268.117

C, 49.25; H, 6.01; N, 20.88; O, 23.86

24584-09-6

Dexrazoxane hydrochloride;149003-01-0; 24584-09-6; 1263283-43-7 (HCl)

71384

White to light yellow solid powder

1.3±0.1 g/cm3

531.5±50.0 °C at 760 mmHg

194-196ºC

275.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.540

-0.37

98.82

2

6

3

19

404

1

C[C@@H](CN1CC(=O)NC(=O)C1)N2CC(=O)NC(=O)C2

BMKDZUISNHGIBY-ZETCQYMHSA-N

InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1

(S)-4,4-(propane-1,2-diyl)bis(piperazine-2,6-dione)

ICRF-187 (ADR-529) HCl; (+)-Razoxane hydrochloride, ADR-529 hydrochloride, Cardioxan, Dexrazoxane HCl, Dexrazoxane hydrochloride, ICRF-187 hydrochloride, Savene; ADR529; ADR-529; ADR 529; ICRF-187; ICRF187; ICRF 187; NSC169780; NSC-169780; NSC 169780; Cardioxan; Cardioxane; US brand names: Totect; Zinecard. Foreign brand names: Cardioxane Savene.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.32 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (9.32 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (9.32 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。