There are many classes of anti cancer chemotherapy drugs. Some of them are cell cycle specific some are not. They act in different ways. One of the subclass is antitumor antibiotics. Topoisomerases are nuclear enzymes that regulate the three dimensional shapes of DNA by cleaving and relegating DNA during replication, transcription, repair, and recombination. Topoisomerase I catalyze cleavage and relegation of single strands of DNA, whereas topoisomerase II regulates breakage and rejoining of both strands. Anthracyclines are topoisomerases II inhibitors.
Antitumor Antibiotics
Most are natural products isolated from group of soil microorganisms, Streptomyces.
Includes-
- Anthracyclines- Doxorubicin, Daunorubicin, Idarubicin
- Mitoxantrone
- Bleomycin
- Dactinomycin
The anthracyclines, doxorubicin, daunomycin (daunorubicin), and idarubicin, are highly pigmented compounds.
- Intercalation into DNA: Anthracyclines insert themselves between DNA base pairs, disrupting DNA structure and inhibiting DNA replication and transcription.
- Topoisomerase II inhibition: These drugs stabilize the DNA-topoisomerase II complex during DNA replication, preventing the re-ligation of DNA strands and resulting in double-strand breaks, leading to apoptosis.
- Generation of Reactive Oxygen Species (ROS): Anthracyclines undergo redox cycling, producing free radicals that cause oxidative damage to DNA, lipids, and proteins, contributing to cytotoxicity.
Membrane Disruption: They interact with cell membranes, altering membrane fluidity and ion transport, which can further promote cell death.
Dose reduction be reserved for patients with multiple liver function test abnormalities or direct bilirubin elevations. The anthracyclines are eliminated by biotransformation (primarily hepatic) and biliary excretion. Renal excretion accounts for only 5% to 15% of total drug clearance.
Why Anthracyclines are called antibiotics?
Anthracyclines (doxorubicin, daunorubicin, idarubicin) are called antibiotics because they were originally isolated from soil-dwelling Streptomyces species—true microorganisms that naturally produce antibacterial compounds. Their birth origin is microbial, even though in oncology we now use them entirely for cytotoxic, antineoplastic effects.
Mechanistically they behave like classic antibiotics at the molecular level:
• They intercalate into DNA
• They inhibit topoisomerase II
• They generate free radicals
These are all actions typical of antibiotic → DNA-active compounds.
But they’re too toxic for routine antibacterial use, so they ended up as chemotherapy instead of in the infectious-disease cupboard.
Price in Bangladesh:
Daunorubicin 20mg/10 ml produced by Beacon Pharma RUBICIN- 600/= Taka
Doxorubicin Produced by Beacon Pharma 50mg/25ml (1000/=), 10mg/5ml (300/=)
Idarubicin by ZAS Corporation 10mg/10ml-15000/= Company Phone number for lower price-01533-85-95-27
Toxicity:
The acute toxicities of the anthracyclines include myelosuppression, mucositis (less prominent with daunomycin), nausea, vomiting, diarrhea, and alopecia. Extravasation of these agents leads to severe local tissue damage and deep ulcerations. Anthracyclines can cause acute and chronic cardiac toxicity. The acute form is characterized by arrhythmias and conduction abnormalities, but there can also be an acute drop in left ventricular function, reaching a nadir at 24 hours.
Toxicity:
- Myelosuppression
- Nausea and vomiting
- Diarrhea
- Mucositis
- Cardiotoxicity-
Acute form- Arrhythmia, conduction abnormalities, pericarditis, myocarditis
Chronic form- Dilated cardiomyopathy, CCF. (cumulative dose>450 mg/m2 for Doxorubicin and >700 mg/m2 for Daunorubicin) - Alopecia
Extravasation:
Because doxorubicin is a strong vesicant, administer slowly with a rapidly flowing IV. Avoid using veins over joints or in extremities with compromised venous and/or lymphatic drainage. If extravasation is suspected, immediately stop infusion, withdraw fluid, elevate extremity, and apply ice to involved site. May administer local steroids. In severe cases, consult a plastic surgeon.
Cardiotoxicity
- Monitor cardiac function before (baseline) and periodically during therapy with echocardiogram to assess LVEF.
- Risk of cardiotoxicity higher in children younger than 5 years, pre-existing heart diseases, prior radiation therapy.
- Risk of cardiotoxicity is decreased with weekly or continuous infusion schedules
- Cardiotoxic effect of doxorubicin are inhibited by the iron chelating agent dexrazoxane (dose 10 mg for 1 mg doxorubicin)
- Enalapril (ACE inhibitor) prevent the late decline LVEF.
- Carvedilol (beta blocker) has cardioprotective effect through its anti-oxidant properties
Clinical and subclinical cardiac toxicity, as measured by:
- Incidence of congestive heart failure.
- Decline in left ventricular ejection fraction below 50% or a decline >10% from baseline.
- Elevated B-type natriuretic peptide (BNP) or NT-pro BNP levels.
- Cardiac MRI: Gold standard for detecting myocardial fibrosis and structural damage.
- Elevated cardiac troponin I or T reflects myocardial injury and can predict early toxicity
- ECG: May show nonspecific changes such as QT prolongation, T-wave flattening, or arrhythmias.
European Medicines Agency (EMA) restricted the use of dexrazoxane in children with cancer because of concerns for increased risk of second malignant neoplasms.
Further reading:
Anthracycline Antibiotics- Linkspringer PDF Available
Here is a quick link to previous topics.
Chemotherapy drugs: Things you need to know
Chemotherapy Drugs for Childhood Cancer Part 2: Basics
Chemotherapy Drugs for Childhood Cancer Part 3 Basics
Chemotherapy Drugs for Childhood Cancer Part 4 Basics
Chemotherapy Drugs Cyclophosphamide Cisplatin Carboplatin
Chemotherapy Drugs for Childhood Cancer Vincristine
