Dexrazoxane

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Dexrazoxane
Dexrazoxane.svg
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MedlinePlus a609010
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administration 		Intravenous
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Identifiers
  • 4-[(2S)-2-(3,5-Dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
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Chemical and physical data
Formula C11H16N4O4
Molar mass 268.273 g·mol−1
3D model (JSmol)
  • O=C2NC(=O)CN(C[C@@H](N1CC(=O)NC(=O)C1)C)C2
  • 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 Yes check.svgY
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Dexrazoxane hydrochloride (Zinecard, Cardioxane) is a cardioprotective agent. It was discovered by Eugene Herman in 1972. The IV administration of dexrazoxane is in acidic condition with HCl adjusting the pH. [1]

Contents

Uses

Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as anthracyclines, [2] such as daunorubicin or doxorubicin or other chemotherapeutic agents. [3] However, in July 2011 the European Medicines Agency (EMA) released a statement restricting use only in adult patients with cancer who have received > 300 mg/m2 doxorubicin or > 540 mg/m2 epirubicin and general approval for use for cardioprotection. [4] [5] That showed a possibly higher rate of secondary malignancies and acute myelogenous leukemia in pediatric patients treated for different cancers with both dexrazoxane and other chemotherapeutic agents that are associated with secondary malignancies. [6] On July 19, 2017, based on evaluation of the currently available data the European Commission issued an EU-wide legally binding decision to implement the recommendations of the Committee for Medicinal Products for Human Use (CHMP) on dexrazoxane and lifted its 2011-contraindication for primary prevention of anthracycline-induced cardiotoxicity with dexrazoxane in children and adolescents where high doses (≥ 300 mg/m3) of anthracyclines are anticipated.

Dexrazoxane was designated by the US FDA as an orphan drug for "prevention of cardiomyopathy for children and adults 0 through 16 years of age treated with anthracyclines". [7] This decision allows virtually all children to receive dexrazoxane starting with the first dose of anthracycline at the discretion of the treating provider. The label change by the agency announcing dexrazoxane as an approved cardio-oncology protectant has been followed by a review by the agency. [8] Currently, the only FDA and EMA approved cardioprotective treatment for anthracycline cardioprotection is dexrazoxane, which provides effective primary cardioprotection against anthracycline-induced cardiotoxicity without reducing anthracycline activity and without enhancing secondary malignancies. [9]

The United States Food and Drug Administration has also approved a dexrazoxane for use as a treatment of extravasation resulting from IV anthracycline chemotherapy. [10] [11] Extravasation is an adverse event in which chemotherapies containing anthracylines leak out of the blood vessel and necrotize the surrounding tissue.

Mechanism

As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. [12] The exact chelation mechanism is unknown, but it has been postulated that dexrazoxane can be converted into ring-opened form intracellularly and interfere with iron-mediated free radical generation that is in part thought to be responsible for anthryacycline induced cardiomyopathy. [13] It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial drugs. [14]

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Acute lymphoblastic leukemia</span> Blood cancer characterised by overproduction of lymphoblasts

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Acute promyelocytic leukemia</span> Subtype of acute myeloid leukaemia characterised by accumulation of promyelocytes

Acute promyelocytic leukemia is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.

<span class="mw-page-title-main">Idarubicin</span> Anthracycline antileukemic drug

Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake. Similar to other anthracyclines, it also induces histone eviction from chromatin.

<span class="mw-page-title-main">Doxorubicin</span> Chemotherapy medication

Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

<span class="mw-page-title-main">Daunorubicin</span> Chemotherapy medication mostly used for leukaemias

Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. It is administered by injection into a vein. A liposomal formulation known as liposomal daunorubicin also exists.

<span class="mw-page-title-main">Anthracycline</span>

Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

<span class="mw-page-title-main">Epirubicin</span>

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

<span class="mw-page-title-main">Asparaginase</span> Enzyme used as medication and in food manufacturing

Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). It is given by injection into a vein, muscle, or under the skin. A pegylated version is also available. In food manufacturing it is used to decrease acrylamide.

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ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, replacing the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:

<span class="mw-page-title-main">Dasatinib</span> Chemical compound

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<span class="mw-page-title-main">Pixantrone</span> Chemical compound

Pixantrone is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.

<span class="mw-page-title-main">Pirarubicin</span> Chemical compound

Pirarubicin (INN) is an anthracycline drug. An analogue of the anthracycline antineoplastic antibiotic doxorubicin. Pirarubicin intercalates into DNA and interacts with topoisomerase II, thereby inhibiting DNA replication and repair and RNA and protein synthesis. This agent is less cardiotoxic than doxorubicin and exhibits activity against some doxorubicin-resistant cell lines.

VAMP regimen or VAMP chemotherapy is a four-drug combination chemotherapy regimen, used today in the treatment of Hodgkin lymphoma. It was one of the earliest combination chemotherapy regimens, originally developed as a treatment for childhood leukemia by a group of researchers at the National Cancer Institute led by Emil Frei and Emil Freireich. The first clinical trial of VAMP began in 1961. Because it was the first time that four chemotherapeutic agents were used at once, the trial was highly controversial at its time. Although new combination chemotherapy regimens have replaced the use of VAMP in the treatment of childhood leukemia, VAMP is considered an important precursor to modern treatments, confirming the effectiveness of combination chemotherapy and leading to the use of combination chemotherapy regimens to treat other types of cancer.

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<span class="mw-page-title-main">Nirali N. Shah</span> American physician-scientist and pediatric hematologist-oncologist

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<span class="mw-page-title-main">Bisantrene</span> Chemical compound

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References

  1. ↑ "Zinecard (Dexrazoxane): Side Effects, Interactions, Warning, Dosage & Uses".
  2. ↑ Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, et al. (July 2004). "The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia". The New England Journal of Medicine. 351 (2): 145–53. doi:10.1056/NEJMoa035153. PMID   15247354.
  3. ↑ Bjelogrlic SK, Radic J, Radulovic S, Jokanovic M, Jovic V (December 2007). "Effects of dexrazoxane and amifostine on evolution of Doxorubicin cardiomyopathy in vivo". Experimental Biology and Medicine. 232 (11): 1414–24. doi:10.3181/0705-RM-138. PMID   18040065. S2CID   20119026.
  4. ↑ Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS, et al. (February 2007). "Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease". Journal of Clinical Oncology. 25 (5): 493–500. doi:10.1200/JCO.2005.02.3879. PMID   17290056.
  5. ↑ Salzer WL, Devidas M, Carroll WL, Winick N, Pullen J, Hunger SP, Camitta BA (February 2010). "Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group". Leukemia. 24 (2): 355–70. doi:10.1038/leu.2009.261. PMC   4300959 . PMID   20016527.
  6. ↑ "FDA Statement on Dexrazoxane". Food and Drug Administration .
  7. ↑ "Orphan drug designations and approvals" . Retrieved June 7, 2019.
  8. ↑ "Cardioxane". 2018-09-17.
  9. ↑ Reichardt P, Tabone MD, Mora J, Morland B, Jones RL (October 2018). "Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling". Future Oncology. 14 (25): 2663–2676. doi: 10.2217/fon-2018-0210 . PMID   29747541.
  10. ↑ Totect label on FDA's website
  11. ↑ Kane RC, McGuinn WD, Dagher R, Justice R, Pazdur R (April 2008). "Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy". The Oncologist. 13 (4): 445–50. doi:10.1634/theoncologist.2007-0247. PMID   18448560. S2CID   7753443.
  12. ↑ Jones RL (November 2008). "Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity". Expert Review of Cardiovascular Therapy. 6 (10): 1311–7. doi:10.1586/14779072.6.10.1311. PMID   19018683. S2CID   25950994.
  13. ↑ "ZINECARD- dexrazoxane hydrochloride injection, powder, lyophilized, for solution". Pharmacia and Upjohn Company LLC.
  14. ↑ Loyevsky M, Sacci JB, Boehme P, Weglicki W, John C, Gordeuk VR (February 1999). "Plasmodium falciparum and Plasmodium yoelii: effect of the iron chelation prodrug dexrazoxane on in vitro cultures". Experimental Parasitology. 91 (2): 105–14. doi:10.1006/expr.1998.4371. PMID   9990337.
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