Pdf longterm testicular toxicity caused by doxorubicin. Some studies have shown that this drug causes apoptosis of male germ cells. Doxorubicin adriamycin was administered by continuous infusion to reduce peak plasma levels and thus lessen cardiac toxicity. Reduction of doxorubicin cardiotoxicity by prolonged.
It is best to read this information with our general information about chemotherapy and the type of cancer you have. Liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated favorable toxicity profiles with better cardiac safety and less myelosuppression, alopecia, nausea and vomiting compared with the conventional anthracyclines. Doxorubicin causes the generation of free radicals and the induction of oxidative stress, associated with cellular injury. Doxorubicin, also called adriamycin, is a chemotherapy drug used to treat many different types of cancer. Doxorubicin is an anthracycline antibiotic with antineoplastic activity. Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a doserelated cardiotoxicity that can lead to heart failure in a subset of.
Comparative pharmacokinetics of free doxorubicin and. Doxorubicin must not be given by the intramuscular or subcutaneous route. Therefore, a bioind is required for bioequivalence studies of a doxorubicin hcl liposomal injection to ensure the safety of human test subjects 1 q1 qualitative sameness means that the test product uses the same inactive ingredients as the reference product. Doxorubicin generates free radicals and induces oxidative stress associated with cellular injury. Curcumin, doxorubicin combo in relapsedrefractory multiple. Doxorubicin hydrochloride investigated as a drug, mutagen, natural product, reproductive effector, and tumorigen. Doxorubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. Vomiting usually occurred one to two times while the doxorubicin was being injected and stopped when drug administration was discontinued. Interpatient variability clearance reduced in obese patients i. The irondoxorubicin complex can bind dna and cell membranes producing free radicals that immediately cleave dna and cell membranes. Clinical studies of liposomeencapsulated doxorubicin.
Although dexrazoxane reduces toxicity when given with doxorubicin, efficacy. Skin is the largest organ in the human body, and which protects organism against unfavorable external factors e. One of these strategies is the use of dexrazoxane also known as icrf187, an adjunctive agent derivative of ethylenediaminetetraacetic acid edta, which acts as a free. See the end of this leaflet for a complete list of ingredients in doxorubicin hydrochloride injection, usp. Such doses may cause acute myocardial degeneration within 24 hours and severe myelosupression, the effects of which are greatest between 10 and 15 days after administration. Only select registry of toxic effects of chemical substances rtecs data is presented here. Doxorubicin induced cardio toxicity cardiotoxicity is a major limiting factor in the use of dxr, thus remains a clinical dilemma in oncology and cardiology practice and has severely limited raises the possibility that histamine may be a mediator of dxrinduced cardiotoxicity 4647. Jun 04, 2012 doxorubicin is a prescription medication used to treat certain types of cancer in adults and children including breast cancer, lung cancer, and ovarian cancer.
The anthracycline doxorubicin dox is widely used in chemotherapy due to its efficacy in fighting a wide range of cancers such as carcinomas, sarcomas and hematological cancers. Furthermore, the free dox concentrations are to be obtained independently and not. Tell your doctor if you have unusual bruising or bleeding, or signs of infection fever, chills, body aches. See the end of this leaflet for a complete list of ingredients in doxorubicin. Nutrients free fulltext possible mechanisms of the. Assessment of late left ventricular dysfunction by radionuclide cineangiography, gottdiener and associates 1 have described persistent left ventricular dysfunction in patients treated with cumulative doses of doxorubicin from 480 to 550 mgm 2 of body surface area.
Adriamycin must not be given by the intramuscular or subcutaneous route. It has been shown that free radicals and oxidative stress are involved in doxorubicininduced cardiotoxicity. Finding a way to maintain the efficacy and reduce toxicity has been one of the major areas of focus of anthracycline research. In four patients, doxorubicin has demonstrated doseindependent pharmacokinetics in the dose range of 30 to 70 mgm 2. Further, it has been shown that free radicals are involved in doxorubicin induced toxicity. Use doxorubicin injection 2 mgml, or doxo rubicin powder for injection. Congestive heart failure in patients treated with doxorubicin. The risk of developing chf increases with increasing total cumulative doses of doxorubicin in excess of 450 mgm delayed cardiotoxicity may occur in patients with prior mediastinal irradiation, in those on concurrent cyclophosphamide therapy, or in those with preexisting heart disease. Toxicity may also occur at a lower cumulative dose in patients. The hydrochloride salt form of doxorubicin, not the free base, is used in the doxorubicin. The initial distribution halflife of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal halflife. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary.
Because free radicals are also known to stimulate the. Side effects include bone marrow depression, alopecia. Dec 31, 2019 you are allergic to certain other anticancer medicines, doxorubicin hydrochloride, or any other ingredient in doxorubicin hydrochloride injection, usp. Pegylated liposomal doxorubicin pld is an anthracyclines derivative with reducing severity of cardiotoxicity and myelosuppression but with localized skin lesions on the palms and the soles ppe. Research open access comparison of safety and toxicity of. The molecule is amphoteric, containing acidic 66 functions in the ring phenolic groups and a basic function in the sugar amino group. Human induced pluripotent stem cellderived cardiomyocytes.
Recent advances in protection against doxorubicininduced. It is often used together with other chemotherapy agents. Doxorubicin pi may 8, 2003 3 65 sugar, producing a hydrophilic center. Comparison of the cardiotoxic effects of liposomal doxorubicin tlc d99 versus free. Objectives the frontline drug doxorubicin has been used for treating cancer for over 30 years. Doxorubicin should be administered only under the super vision of a physician who is experienced in the use of cancer. Doxorubicin side effects, uses, dosage, overdose, pregnancy. Anticancer antibiotics details the development of doxorubicin as a widespectrum antitumor antibiotic. Despite prolonged use and relatively large cumulative doses of.
Research open access comparison of safety and toxicity of liposomal doxorubicin vs. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first. Doxorubicin toxicity annals of internal medicine american. The good news is that there is a long and growing list of conventional, fda approved therapies for the treatment of multiple myeloma mm. Since several mechanisms are involved in the development of cardiac toxicity, different strategies are being performed to prevent doxinduced cardiomyopathy. Prolonged pegylated liposomal doxorubicin treatment for. The role of doxorubicin in potential ovarian failure remains obscure.
Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure chf may occur either dur dosage should be reduced in patients with impaired hepatic function. Gastrointestinal toxicity vomiting occurred during doxorubicin infusion in 8 of 56 treatments. Your doctor will talk to you about this treatment and its possible side effects before you agree consent to have. Pad is an active salvage therapy with manageable toxicity in patients with relapsedrefractory multiple myeloma. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure chf may occur either during therapy or months to years after termination of therapy. Toxicity may also occur at a lower cumulative dose in. Dilute in 250 to 1,000 ml of ns, 5% dextrose in water d5w, or a saline dextrose solution for continuous infusion or bolus.
While pld has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of pld and free doxorubicin in sarcoma. Longterm cure of soft tissue sarcoma with pegylated. Doxorubicin induces cardiotoxicity through upregulation of. Doxorubicin hydrochloride doxorubicin hydrochloride this product information is intended only for residents of the united states.
A cumulative treatment dose of 350 mgm2 of free dox shows a. Doxorubicin is a prescription medication used to treat certain types of cancer in adults and children including breast cancer, lung cancer, and ovarian cancer. There are two main theories i ironrelated free radicals and formation of. Severe local tissue necrosis will occur if there is extravasation during administration. Doxorubicin may cause dangerous effects on your heart.
Doxorubicin, sold under the trade names adriamycin among others, is a chemotherapy medication used to treat cancer. Oct 02, 2019 doxorubicin can weaken your immune system. It binds 67 to cell membranes as well as plasma proteins. The exact mechanism of cardiotoxicity of doxorubicin is somewhat controversial. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or. Single doses of 250 mg and 500 mg of doxorubicin have proved fatal. If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them.
Doxorubicin belongs to a group of drugs called anthracyclines, which slow and stop the growth of cancer cells. Skin toxicity in the course of anticancer treatment occurs in majority of patients and may substantially reduce quality of life. Due to its required high doses, it poses severe toxicity, such as cardiotoxicity and nephrotoxicity. Comparison of safety and toxicity of liposomal doxorubicin. Effects of caffeic acid on doxorubicin induced cardiotoxicity. Four versus six cycles of cyclophosphamidedoxorubicin or. In their excellent paper doxorubicin cardiotoxicity. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Congestive heart failure in patients treated with doxorubicin a retrospective analysis of three trials sandra m. Doxorubicin dox, an antineoplastic drug, has been extensively used for the treatment of different cancers. In the current draft guidance, the bioequivalence assessment relies on t he analysis of liposome encapsulated doxorubicin and unencapsulated doxorubicin free dox in plasma. Doxorubicin, isolated from the bacterium streptomyces peucetius var.
The protective effects of silymarin against doxorubicin. The book begins by tracing the discovery and development of doxorubicin, highlighting factors such as a the involvement of organic chemistry at an early stage, which allowed the rapid identification of doxorubicin and ensured its prompt availability for the clinical trials. Jun 21, 2019 the total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin, and mitoxantrone. While providing a cure in select cases, doxorubicin causes toxicity to most major organs.
Free radicalindependent cytotoxicity mechanisms, taking place in the nuclear compartment of the cell, may more likely be involved in the antitumor effect of doxorubicin. In this report, we describe a patient with highgrade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin. There are two proposed mechanisms by which doxorubicin acts in the cancer cell i intercalation into dna and disruption of topoisomeraseiimediated dna repair and ii generation of free radicals and their damage to cellular membranes, dna and proteins shown in fig. Jan 27, 2003 patients must be disease free from prior malignancies for 5 years, except for curatively treated basal cell or squamous cell carcinoma of the skin or carcinomainsitu of the cervix. Risk factors for cardiotoxicity induced by anthracyclines. Free radicaldependent toxicity mechanisms of doxorubicin 220 2. Pdf insights into mechanisms of doxorubicin cardiotoxicity. The hypothesis proposed was that if doxorubicin cardiotoxicity and hepatotoxicity are related to free radical formation and oxidative stress, an antioxidant such as silymarin may protect against doxorubicin induced toxicity. Although maximally cytotoxic in s phase, doxorubicin is not cell cyclespecific.
Doxorubicin is a potent drug widely used against different types of cancer and can cause damage to healthy tissues. Pdf compatibility and stability of vincristine sulfate. Comparative study of the antitumor activity of free. Serious irreversible myocardial toxicity with delayed congestive. A comparison of liposomal formulations of doxorubicin with. Doxorubicin hydrochloride doxorubicin hydrochloride pfizer. Call your doctor at once if you feel very weak or tired, or have fast heartbeats, shortness of. Although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. Jan 15, 2019 while pld has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of pld and free doxorubicin in sarcoma. Product information adriamycin solution for injection warnings 1.
Assessment of late left ventricular dysfunction by radionuclide cineangiography, gottdiener and associates 1 have described persistent left ventricular dysfunction in patients treated with cumulative doses of doxorubicin. Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy. The book begins by tracing the discovery and development of doxorubicin. Doxorubicin fda prescribing information, side effects. The incidence of ppe was similar in both arms or 1. Overview of comments received on pegylated liposomal.
However, these results are still inferior to the observations in rodents of a twofold decrease in the toxic ity of doxorubicin. Comparative study of the antitumor activity of free doxorubicin and polyethylene glycolcoated liposomal doxorubicin in a mouse lymphoma model1 anna cabanes, dinah tzemach, dorit goren. Doxorubicin adriamycin, rubex chemotherapy drug information. Doxorubicin hydrochloride for injection, usp 3 doxorubicin.
See actual entry in rtecs for complete information. The authors declare that they have no conflict of interest. Molecular mechanisms of doxorubicininduced cardiotoxicity. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electron microscopy. Skin toxicity after palliative chemotherapy containing. Dox is hydrophilic and therefore distributes to normal organs at a faster rate. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Extravasation of doxorubicin hydrochloride can result in severe local tissue injury and necrosis requiring wide excision of affected area and skin grafting. Doxorubicin is an anthracycline that exerts its antineoplastic effects by way of a number of mechanisms, including topoisomerase ii inhibition, intercalation of dna, and generation of free radicals. Liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated favorable toxicity profiles with better. Doxorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to dna. The iron doxorubicin complex can bind dna and cell membranes producing free radicals that immediately cleave dna and cell membranes.
First isolated in the early 1960s, doxorubicin dox is among the most effective anticancer agents ever developed. Dox has been used mainly for the treatment of breast cancer, solid tumors in children, soft tissue sarcomas, and aggressive lymphomas. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. Doxorubicin is an anticancer antineoplastic or cytotoxic chemotherapy drug. The dose of doxorubicin was escalated from 30 mgm2 7.
It has one of the widest spectrums of antitumor activity of any antineoplastic agent and is administered intravenously as the hydrochloride salt. Doxorubicin causes the generation of free radicals and the induction of oxidative stress, associated with. Recent advances in protection against doxorubicininduced toxicity. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Although dexrazoxane reduces toxicity when given with doxorubicin, efficacy is also reduced so this combination is used only after a cumulative dose threshold has been reached. The good news is that there is a long and growing list of. The goal of this study is to investigate the cardioprotective effects of caffeic acid on doxorubicin induced cardiotoxicity. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of cu ii and fe iii reduction at the cellular level. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. The hydrochloride salt form of doxorubicin, not the free base, is used in the doxorubicin formulation for use in humans. Doxorubicin and dacarbazine ad regimen for soft tissue sarcomas. Our studies demonstrate that the pharmaco kinetics of drug entrapped in liposomes is greatly altered thereby providing a significantly reduced toxicity as compared to free doxorubicin. Comparison of safety and toxicity of liposomal doxorubicin vs. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life.
This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely doxil and myocet. Vomiting usually occurred one to two times while the doxorubicin. In this report, we describe a patient with highgrade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Doxorubicin fda prescribing information, side effects and uses.
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