Iron chelator; cardioprotective agent

Dexrazoxane combined with doxorubicin, daunorubicin, or idarubicin reduces the tissue lesions in B6D2F1 mice (expressed as area under the curve of wound size times duration) by 96%, 70%, and 87%, respectively. Dexrazoxane combined with doxorubicin, daunorubicin, or idarubicin results in a statistically significant reduction in the fraction of mice with wounds as well as the duration of wounds.

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Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients[3].

Cells were treated with 0.1% DMSO (solvent control) or 200 μmol/L Dexrazoxane for 5 h followed by coincubation with doxorubicin for 1 day or VP-16 for 2 days. MTT (0.1 mg) was then added to each well and cells were incubated for an additional 4 h at 37°C. After removal of medium, DMSO was added and absorbance at 570 nm was measured using the Microplate Reader. Average IC50 values (mean ± SE) were determined in triplicate or quadruplicate.[1]

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Neutral comet assay. Primary MEFs were treated with DMSO or doxorubicin for 1.5 h in a CO2 incubator at 37°C followed by additional 30-min incubation in fresh medium to reverse Top2 cleavage complexes. H9C2 cells were treated with DMSO or Dexrazoxane (100 μmol/L) for 3 h, washed, and replenished with fresh medium. Cells were then treated with DMSO or doxorubicin for 1.5 h followed by additional 30-min incubation in fresh medium to reverse Top2 cleavage complexes. Cells were then washed and trypsinized using 0.005% trypsin and resuspended in DMEM supplemented with 10% FetalPlex animal serum complex (10,000/mL). Cell suspension (50 μL) was then mixed with 500 μL 0.5% low-melting point agarose at 37°C. Cell/agarose mixture (75 μL) was transferred onto glass slides. Slides were then immersed in prechilled lysis buffer [2.5 mol/L NaCl, 100 mmol/L EDTA, 10 mmol/L Tris (pH 10.0), 1% Triton X-100, 10% DMSO] for 1 h followed by equilibration in 1× Tris-borate EDTA (TBE) buffer for 30 min. Slides were electrophoresed in 1× TBE at 1.0 V/cm for 10 min and stained with Vistra Green. Images were visualized under a fluorescence microscope and captured with a charge-coupled device camera. The average comet tail moment was determined from measuring at least 100 cells for each treatment group as described previously. Statistical analysis of the mean comet tail moments was done using Student's t test.[1]

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Band depletion assay. H9C2 cells (1.2 × 105) were treated with 250 μmol/L VP-16 in the presence or absence of Dexrazoxane (150 μmol/L) for 15 min. Cells were either lysed immediately or incubated in drug-free medium for another 30 min at 37°C (to reverse Top2 cleavage complexes) before lysis. Cell lysates were analyzed by Western blotting using the anti-Top2α/Top2β and anti–α-tubulin antibody. The amount of Top2 cleavage complexes can be estimated from the difference between the amount of free Top2 after reversal and the amount of free Top2 without reversal[1].

Mice [3]
\nAll 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.\n

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\nAcute treatment [3]
\nAt 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.\n

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\nBreeding trial [3]
\nFemale 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.\n [3]
br>\n\nFollowing 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
Intravenous administration achieves complete bioavailability. Urinary excretion plays a crucial role in the elimination of dexrazoxane. 42% of a 500 mg/m² dose of dexrazoxane is excreted in the urine.
9 to 22.6 L/m²
7.88 L/h/m² [50 mg/m² doxorubicin and 500 mg/m² dexrazoxane]
6.25 L/h/m² [60 mg/m² doxorubicin and 600 mg/m² dexrazoxane]
Following intravenous administration, the drug rapidly distributes into tissue fluids, with the highest concentrations of the parent drug and its hydrolysates in the liver and kidneys.
At the end of a 15-minute infusion of 500 mg/m² doxorubicin, the mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL. After a rapid distribution phase, dexrazoxane reaches post-distribution equilibrium within 2 to 4 hours.
The estimated steady-state volume of distribution of dexrazoxane indicates that it is primarily distributed in systemic water (25 L/m²).
In vitro studies have shown that dexrazoxane does not bind to plasma proteins.
For more complete data on the absorption, distribution, and excretion of dexrazoxane (9 items), please visit the HSDB record page.

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Metabolites/Metabolites
Dexrazoxane is hydrolyzed in the liver and kidneys by dihydropyrimidine amide hydrolases to active metabolites that bind to metal ions.
Metabolites include the active drug, diacid-diacid cleavage products, and two monoacid-monoamide cyclic products of unknown concentration.
In vitro studies have shown that dexrazoxane is hydrolyzed in the liver and kidneys by dihydropyridinase (DHPase), but not in the heart extract. This study aimed to determine the metabolism of dexrazoxane (ICRF-187) into monocyclic open-ring hydrolysates and bicyclic open-ring metal chelates (ADR-925) in brain metastases treated with high-dose etoposide. In this phase I/II clinical trial, dexrazoxane was used as a rescue agent to reduce the extracranial toxicity of etoposide. High-performance liquid chromatography (HPLC) was used to determine dexrazoxane and its monocyclic open-ring hydrolysates, and fluorescence flow injection assay was used to determine ADR-925. Following dexrazoxane infusion, both monocyclic open-ring hydrolysates appeared in plasma at low concentrations, which then rapidly decreased, with half-lives of 0.6 hours and 2.5 hours, respectively. A plasma ADR-925 concentration of 10 μM was detected after the intravenous infusion of dexrazoxane, indicating rapid metabolism of dexrazoxane in vivo. The plasma concentration of ADR-925 plateaued at 30 μM for 4 hours before slowly decreasing. The pharmacokinetics of dexrazoxane are similar to other reported low-dose data under different conditions. The rapid appearance of ADR-925 in plasma may enable its uptake by cardiac tissue and binding of free iron. These results indicate that the dexrazoxane intermediate is enzymatically metabolized to ADR-925, providing a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane. Dexrazoxane is hydrolyzed in the liver and kidneys by dihydropyrimidine amide hydrolases to an active metabolite capable of binding to metal ions. Elimination pathway: Urinary excretion plays a significant role in the elimination of dexrazoxane. 42% of a 500 mg/m² dose of dexrazoxane is excreted in the urine. Half-life: 2.5 hours. The distribution half-life is approximately 12 to 60 minutes… Elimination - 2.5 hours.

Toxicity Summary
The mechanism by which dexrazoxane exerts its cardioprotective effect is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Laboratory studies have shown that dexrazoxane (a prodrug) is converted intracellularly into an open-ring bidentate chelator that chelates free iron and interferes with iron-mediated free radical generation, which is considered to be partly responsible for anthracycline-induced cardiomyopathy. Notably, dexrazoxane may also exert its protective effect through its inhibition of topoisomerase II. Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of dexrazoxane during lactation. The manufacturer recommends that women refrain from breastfeeding during treatment and for two weeks after the last dose of dexrazoxane. However, due to the combined use of dexrazoxane and doxorubicin, the withdrawal period may be longer depending on the doxorubicin dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Very low (< 2%)

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Toxicity data
Humans (intravenous): TDLo: 383 mg/kg
Mice (intraperitoneal): LDLo 800 mg/kg
Dogs (intravenous): LDLo: 2 g/kg
Mice intraperitoneal LD₁₀ = 500 mg/kg. Intravenous, dogs LD₁₀ = 2 g/kg.

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Interaction
In a crossover study of cancer patients, the pharmacokinetics of doxorubicin (50 mg/m²) and its major metabolite doxorubicinol were not significantly altered in the presence of dexorubicin (500 mg/m²).

[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.

(+)-Dexazosen is a razorzene compound. It has dual effects as a chelating agent, antitumor drug, cardiovascular drug, and immunosuppressant. Dexazosen is a cytoprotective agent. Dexazosen is a didioxanone compound with iron-chelating, chemoprotective, cardioprotective, and antitumor activities. Upon hydrolysis, dexazosen is converted to an active form similar to ethylenediaminetetraacetic acid (EDTA), chelating iron and thus limiting the formation of anthracycline-iron complexes by free radicals, which may minimize anthracycline-iron complex-mediated oxidative damage to the heart and soft tissues. The drug also inhibits the catalytic activity of topoisomerase II, thereby inhibiting tumor cell growth. It is an antimitotic agent with immunosuppressive properties. Dexazosen (the (+)-enantiomer of razorzene) protects the heart from anthracycline toxicity. It appears to inhibit the formation of toxic iron-anthracycline complexes. The U.S. Food and Drug Administration (FDA) has designated dexrazoxane as an orphan drug for the prevention or reduction of the incidence and severity of anthracycline-induced cardiomyopathy.
Dexrazoxane's (+)-enantiomer.
See also: Dexrazoxane hydrochloride (salt form).
Indications
For the reduction of the incidence and severity of doxorubicin-induced cardiomyopathy in female patients with metastatic breast cancer who have received a cumulative dose of up to 300 mg/m² doxorubicin hydrochloride and who would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation of intravenously administered anthracyclines.
FDA Label
Savene is indicated for the treatment of anthracycline extravasation.
Mechanism of Action
The mechanism by which dexrazoxane exerts its cardioprotective effect has not been fully elucidated. Dexrazoxane is a cyclic derivative of EDTA and readily penetrates cell membranes. Laboratory studies have shown that dexazosin (a prodrug) is converted intracellularly into an open-ring bidentate chelator, which chelates free iron and interferes with iron-mediated free radical generation, which is considered to be partly responsible for anthracycline-induced cardiomyopathy. Notably, dexazosin may also exert its protective effect through its inhibition of topoisomerase II. The mechanism of dexazosin's cardioprotective effect is not fully elucidated. Dexazosin is a cyclic derivative of ethylenediaminetetraacetic acid (EDTA) and readily penetrates cell membranes. Laboratory studies have shown that dexazosin is converted intracellularly into an open-ring chelator, interfering with iron-mediated free radical generation, which is considered to be partly responsible for anthracycline-induced cardiomyopathy.

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Therapeutic Use
Cardioprotective Agent
Dexazosin is indicated for reducing the probability and severity of cardiomyopathy in female patients with metastatic breast cancer receiving doxorubicin treatment. These patients had received a cumulative dose of doxorubicin at 300 mg/m² body surface area and were able to benefit from continued doxorubicin treatment. /US product label contains/
/Experimental Treatment:/ Accidental extravasation of anthracycline-containing chemotherapy drugs often leads to extensive tissue necrosis, resulting in serious complications. Therefore, treatment methods include extensive surgical debridement. We report a case of a 41-year-old female breast cancer patient who experienced epirubicin extravasation. She received three consecutive days of intravenous dexazosin and recovered without surgery, with only mild sensory abnormalities in the surrounding tissues. Although dexazosin infusion for this indication is still in the experimental stage, we consider it a promising treatment option for patients with accidental anthracycline extravasation.

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Drug Warning
Dexazosin is not recommended for initiation of doxorubicin treatment. Due to the potential interference with the antitumor efficacy of this regimen, concomitant use of dexazosin at the initiation of a fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is not recommended.
FDA Pregnancy Risk Classification: C / Risk cannot be ruled out.
There is a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
Dexazosen may exacerbate myelosuppression caused by chemotherapy drugs.
Do not use in combination with chemotherapy regimens that do not contain anthracyclines.
For more complete data on drug warnings for dexazosen (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
Dexazosen is a cardioprotective agent used in combination with doxorubicin to reduce the risk and severity of cardiomyopathy in women with metastatic breast cancer receiving cumulative doxorubicin therapy. Patients receiving anthracycline antitumor drugs may experience three types of cardiotoxicity: acute and transient; chronic subacute (related to cumulative dose, with a slower onset); and delayed-onset, which mainly occurs in patients who were exposed to the drug in childhood and usually appears several years after treatment. Although the exact mechanism of anthracycline-induced cardiotoxicity remains unclear, multiple mechanisms of action have been confirmed, potentially leading to cardiotoxicity. In animal studies, anthracyclines selectively inhibit the gene expression of cardiac α-actin, troponin, myosin light chain 2, and creatine kinase M isoform. This can lead to myofibril loss, thereby triggering anthracycline-induced cardiotoxicity. Anthracyclines may also cause cardiomyocyte damage through calcium overload, altered myocardial adrenergic function, and the release of vasoactive amines and pro-inflammatory cytokines. Furthermore, studies have shown that the primary cause of anthracycline-induced cardiotoxicity is DNA free radical damage. These drugs can intercalate into DNA, chelate metal ions to form drug-metal complexes, and generate superoxide radicals through redox reactions. Anthracyclines also contain quinone structures, which can be reduced to semiquinone radicals through NADPH-dependent reactions, subsequently triggering a cascade reaction of superoxide and hydroxyl radicals. The chelation of metal ions (especially iron) by anthracyclines forms anthracycline-metal complexes, which can catalyze the generation of reactive oxygen species. This complex is a strong oxidant that can trigger lipid peroxidation even in the absence of oxygen free radicals. Anthracycline-induced toxicity may be exacerbated in cardiomyocytes because these cells lack sufficient amounts of certain enzymes (such as superoxide dismutase, catalase, and glutathione peroxidase), which are involved in scavenging free radicals and protecting cells from subsequent damage. Dexrazoxane hydrochloride is the hydrochloride salt of dioxanepiperazine, which possesses iron-chelating, chemoprotective, cardioprotective, and antitumor activities. Upon hydrolysis, dexrazoxane is converted to an active form similar to ethylenediaminetetraacetic acid (EDTA), chelating iron and thus limiting the formation of anthracycline-iron complexes that generate free radicals. This may minimize anthracycline-iron complex-mediated oxidative damage to the heart and soft tissues. The drug also inhibits the catalytic activity of topoisomerase II, thereby inhibiting tumor cell growth. (+)-Enantiomers of dexrazoxane. See also: Dexrazoxane (with active moiety). Drug Indications Savene is indicated for the treatment of anthracycline extravasation. Doxorubicin is one of the most effective and widely used anticancer drugs in clinical practice. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin treatment. Zinecard (also known as ICRF-187) has been used clinically as a cardioprotective agent against doxorubicin cardiotoxicity. However, the molecular mechanisms of doxorubicin cardiotoxicity and the cardioprotective effects of zezorcard are not fully elucidated. In this study, we found that zezorcard specifically eliminated the doxorubicin-induced DNA damage signal γ-H2AX in H9C2 cardiomyocytes, but had no effect on camptothecin or hydrogen peroxide. The proteasome inhibitors bortezomib and MG132 also specifically eliminated doxorubicin-induced DNA damage, and in top2β(-/-) mouse embryonic fibroblasts (MEFs), DNA damage was significantly reduced compared to TOP2β(+/+) MEFs, suggesting the involvement of the proteasome and DNA topoisomerase IIβ (Top2β). In addition, dexrazoxane, besides antagonizing the formation of the Top2 cleavage complex, can also induce the rapid degradation of Top2β, which is consistent with the reduction of doxorubicin-induced DNA damage. Our results together suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage by interfering with topoisomerase 2β (Top2β), which may suggest that Top2β is involved in the cardiotoxicity of doxorubicin. The specific involvement of the proteasome and Top2β in doxorubicin-induced DNA damage is consistent with the following model: the processing of the doxorubicin-induced Top2β-DNA covalent complex by the proteasome exposes the DNA double-strand breaks hidden by Top2β. [1] The clinical efficacy of anthracycline antitumor drugs is limited by their high incidence of severe and usually irreversible cardiotoxicity, the reasons for which remain controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin at concentrations ≤1 μmol/L can induce programmed cell death of cardiomyocytes within 24 hours, which has been confirmed by various complementary techniques. Conversely, daunorubicin at concentrations ≥10 μmol/L induced necrotic cell death within 24 hours without the characteristic changes of apoptosis observed. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored hydrogen peroxide generation using dichlorofluorescein (DCF). However, daunorubicin (1 μmol/L) did not increase DCF fluorescence intensity, and the combination of the antioxidants N-acetylcysteine or α-tocopherol with ascorbic acid also failed to prevent apoptosis. Conversely, dexrazoxane (10 μmol/L), known to reduce the cardiotoxicity of anthracyclines, prevented daunorubicin-induced cardiomyocyte apoptosis but not necrosis induced by higher concentrations of anthracyclines (≥10 μmol/L). The superoxide dismutase mimic porphyrin manganese (II/III) tetrakis(1-methyl-4-pyridyl)porphyrin (50 μmol/L) mimicked the anti-apoptotic effect of dexrazoxane. The understanding that anthracycline-induced cardiomyocyte apoptosis (possibly mediated by superoxide anion generation) occurs at concentrations far below those leading to cardiomyocyte necrosis may help in designing new treatment strategies to limit the toxicity of these drugs. [2] Dexrazoxin/Dexra can reduce acute DXR-induced ovarian toxicity and improve the fertility window, manifested by increased fertility, offspring weight, litter size, and number of deliveries after DXR treatment. A 1:1 Dexra:DXR dose can protect the ovaries. The easily administered dexmedetomidine (Dexra) provides a timely, economical, and safe method of pharmacological ovarian protection, especially for pre-pubertal and adolescent girls where oocyte and embryo freezing is not a viable fertility preservation option. [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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)