Anthracyclines are drugs extracted from Streptomyces spp. used in the treatment of various types of cancers. The different types available for treatment are -
Non-FDA approved indications include:
The explanations of cytostatic and cytotoxic actions of anthracyclines point to by many different mechanisms including free radical formation, lipid peroxidation, direct membrane effects, and enzyme interactions. The following elucidates some of these theories:
The most widely accepted explanation for the action of anthracyclines is their interaction with topoisomerase-II. The ternary complex thus formed prevents the re-ligation of the ds DNS breaks. Subsequently, it promotes growth arrest and apoptotic cell death.
Anthracyclines have a chromophore moiety that has an intercalating function and inserts between adjacent base pairs of DNA when localized to the nucleus of the cell; this inhibits DNA and RNA synthesis especially in highly replicating cells blocking cell division.
Reactive oxygen species (ROS)
Redox reactions generate reactive oxygen species in the presence of cytochrome P450 reductase, NADH dehydrogenase, and xanthine oxidase - the excess ROS cannot be detoxified resulting in oxidative stress, DNA damage and lipid peroxidation triggering cell apoptosis.
DNA adduct formation
These drugs are known to form adducts with DNA promoted by formaldehyde releasing pro-drugs. The adducts block specific transcription factors and eventually initiate apoptosis.
Pharmacokinetics of the drug:
75% bound to plasma proteins
Primarily excreted into the bile
Does not cross the blood-brain barrier
Mode of administration:
The dosing of anthracyclines is by body surface area and varies with indication and type of anthracycline. The dosage of doxorubicin for common indications are listed below.
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Anthracyclines have many adverse reactions which may range from mild to severe. The incidence rates of these reactions, however, are largely unknown.
Adults, adolescents and, children
Children with BSA less than 0.5m2 should have dose calculated based on body weight.
Dose adjustments are necessary for hepatic impairment.
Anthracyclines are major substrates of CYP2D6 and CYP3A4 substrate. Express caution while using it concurrently with inhibitors of CYP3A4 and CYP2D6.
Antidote for anthracyclines:
Tissue necrosis induced by extravasation of anthracycline can have many complications. Dexrazoxane is an experimental antidote to tackle the effects of extravasation.
It may also help to prevent the development of anthracycline-induced cardiotoxicity.
The administration of anthracyclines requires the efficient functioning of a team of doctors and other health professionals. A general practitioner, oncologist, physician assistant or nurse practitioner, pharmacist, and nurses are usually involved in patient care. A pediatrician and cardiologist may also have involvement as the case may dictate. The primary oncologist usually decides the patient's treatment plan; he or she also counsels the patient on the need for this chemotherapeutic agent and the potential risks. A pharmacist is usually involved during the initial treatment phase to provide the patient information on the dose, adverse effects, monitoring, and follow-up. After the initial phase of treatment, the patient is regularly followed up in the oncology clinic by the oncologist who assesses response to treatment and also monitors the patient for adverse effects. The oncologist may alternate with the physician assistant or the nurse practitioner to see the patient at shorter intervals. A pediatrician may be involved in monitoring growth and development in cases of chemotherapy in children.
The most critical component of the multidisciplinary approach is the involvement of a cardiovascular team in the treatment to prevent anthracycline-induced cardiotoxicity and to manage it effectively. Several studies have shown the benefit of this approach which includes long term care and follow-up in the outpatient setting. One such study provides high-level evidence for the development of guidelines.
|||Megías-Vericat JE,Martínez-Cuadrón D,Sanz MÁ,Poveda JL,Montesinos P, Daunorubicin and cytarabine for certain types of poor-prognosis acute myeloid leukemia: a systematic literature review. Expert review of clinical pharmacology. 2019 Jan 23; [PubMed PMID: 30672340]|
|||Antolín S,Acea B,Albaina L,Concha Á,Santiago P,García-Caballero T,Mosquera JJ,Varela JR,Soler R,Calvo L, Primary systemic therapy in HER2-positive operable breast cancer using trastuzumab and chemotherapy: efficacy data, cardiotoxicity and long-term follow-up in 142 patients diagnosed from 2005 to 2016 at a single institution. Breast cancer (Dove Medical Press). 2019; [PubMed PMID: 30643452]|
|||Meyer M,Seetharam M, First-Line Therapy for Metastatic Soft Tissue Sarcoma. Current treatment options in oncology. 2019 Jan 24; [PubMed PMID: 30675651]|
|||Barbosa RR,Bourguignon TB,Torres LD,Arruda LS,Jacques TM,Serpa RG,Calil OA,Barbosa LFM, Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers. Revista da Associacao Medica Brasileira (1992). 2018 Aug; [PubMed PMID: 30673046]|
|||Pituskin E,Haykowsky M,McNeely M,Mackey J,Chua N,Paterson I, Rationale and design of the multidisciplinary team IntervenTion in cArdio-oNcology study (TITAN). BMC cancer. 2016 Sep 15; [PubMed PMID: 27629548]|