Medical Pharmacology Chapter 33-34: Anticancer Drugs
Topoisomerase Inhibitors Type II: Doxorubicin (Adriamycin)
Overview: anthracycline-type topoisomerase II inhibitors1,7,8
Among the anthracyclines, doxorubicin (Lipodox, Doxil) and daunorubicin (Cerubidine) represent the first agents developed.
These drugs exhibit antineoplastic effects across many malignancies.
Among the cytotoxic class of anticancer drugs, anthracycline antibiotics are very widely employed.
Anthracycline natural product classification is due to their isolation from Streptomyces peucetius variation caesius.
Although doxorubicin and daunorubicin are structurally very similar, doxorubicin exhibits a broader range of anticancer activities compared to daunorubicin.1
Other anthracycline drugs have been developed exhibiting potentially reduced toxicities.
These drugs include:
Daunorubicin and idarubicin have been mainly used in managing acute leukemias.
Doxorubicin and epirubicin are often used in solid tumor treatments.
Doxorubicin and other anthracyclines exhibit four principal means by which cytotoxicity are promoted:
Topoisomerase II inhibition
Generation of oxygen and semiquinone free radicals
DNA intercalation that blocks DNA and RNA synthesis and DNA strand scission
Cellular membrane fluidity and ion transport changes induced by drug-membrane association.3
Anthracyclines, because of potential generation of free radicals, induce a frequently irreversible cardiomyopathy.
The total dose of the drug appears correlated with the likelihood of this cardiomyopathy.
Mitoxantrone, although structurally similar, is associated with reduced cardiotoxicity and appears useful in treating:
Myelogenous leukemia (AML)1,7,8
Doxorubicin (adriamycin) is an anthracycline antibiotic which is both widely used and often employed in management of lymphoma and breast cancer, as well as other solid tumors.
Anticancer mechanisms of action include:
Topoisomerase cleavage complex stabilization
Topoisomerase II enzyme inhibition
Production of reactive (oxygen) intermediates
Promotion of apoptosis.
Doxorubicin may be used in the standard form or in a liposomal formulation.7,8
Usually this agent is administered by the intravenous (IV) route of administration (dose range may be about 30-75 mg/m2 every three weeks).
Doxorubicin is a prominent vesicant and extravasation associated with drug administration can cause skin necrosis as well as necrosis in regional tissue.
Management of this pathology may require both surgery and skin grafts.7,8
Anthracycline-type anticancer agents (e.g. doxorubicin, daunorubicin, epirubicin) are subject to hepatic metabolism and biliary excretion.7
Renal excretion is limited to <10% of the administered parent drug.
For patients exhibiting hepatic dysfunction, doxorubicin dosage reduction may be required depending on the extent to which plasma bilirubin levels is elevated.7
Doxorubicin, daunorubicin, as well as epirubicin and idarubicin, are administered by the intravenous (IV) route of administration.1,7,8
Clearance of the active compound depends on both hepatic metabolism as well as biliary excretion (~50%).
In the process of metabolism anthracyclines e.g. doxorubicin undergo a chemical reduction of side chain carbonyl groups to alcohol with attendant reduction in cytotoxicity.
Additionally, a one-electron reduction results in hydroxyl radicals and superoxide anion production.
A two-electron reduction results in species suitable for biliary excretion.
Doxorubicin exhibits a volume of distribution (Vd) of about 25 L with protein binding on the order of 65%.1,7,8
A multiphasic plasma disappearance curve is characterized by a rapid, initial doxorubicin distribution from plasma, resulting in a t1/2α of about 5-10 minutes.
A second redistribution phase from plasma, t1/2β lasts about two hours.
A final, extended half-life, t1/2γ lasts about 30 hours, likely reflecting substantial binding of doxorubicin both to DNA and tissue cardiolipin.
Known routes of elimination account for about 55% of administered parent drug dose.
Given the importance of hepatic metabolism, drug clearance is reduced in cases of substantial hyperbilirubinemia as well as in those patients with significant metastatic liver tumors.
About 10% of administered doxorubicin exhibits renal clearance.1,7,8
Doxorubicin apparently does not cross the blood-brain barrier.13 (https://www.drugs.com/pro/doxorubicin.html)
Acute toxicities associated with doxorubicin administration include:
G.I. disturbances (nausea/vomiting).
The acute, dose-limiting toxicity is myelosuppression.
Antiemetic drugs are administered along with doxorubicin.
Antiemetic drugs that may be helpful in managing acute emesis associated with chemotherapeutic agents, such as doxorubicin, which are classified as having a high "emetic risk."14 (Navari RM Management of Nausea and Vomiting June 1, 2015;(https://www.cancernetwork.com/cancer-management/management-nausea-and-vomiting)
|Granisetron (Sustol, Sancuso)||Ondansetron (Zofran, Zuplenz)||Palonosetron (Aloxi)|
|Dexamethosone (Ozurdex et al)||Metochlopramide (Reglan)||Haloperidol (Haldol)|
|Dronabinol (Syndros, Marinol)||Nabilone (Cesamet)||Prochlorperazine (Compro)|
|Lorazepam (Atavan)||Natupitant (Akyneo [natupitant + palonosetron])||Aprepitant/Fosaprepitant. Pro-drug (Emend)|
Extended infusion time reduces both nausea and likelihood of cardiotoxicity.
As noted above, doxorubicin is a significant vesicant and following extravasation significant skin necrosis may occur.
Accordingly, infusions through a central venous catheter is likely appropriate.
Acute and Chronic Toxicities:8
Cardiotoxicity is both an acute and chronic associated with doxorubicin administration .
Cardiac toxicity may occur even though the drug remains effective in tumor treatment.
Cardiotoxicity may occur associated with anthracycline-based anticancer agents given alone or in combination with other chemotherapy.
Furthermore, cardiotoxicity is also associated with the monoclonal anticancer antibody, trastuzumab (Herceptin).
The combination of anthracycline and trastuzumab, in patients with tumors expressing high HER2/neu levels, is contraindicated due to enhancement of anthracycline -related cardiac damage by trastuzumab.
Use of doxorubicin in treating children is particularly problematic given increased pediatric patients sensitivity to cardiotoxic effects.8
Acute cardiotoxicity due to doxorubicin clinically presents usually as arrhythmias which may include heart block.
Most serious presentations are described by a pericarditis-myocarditis syndrome characterized by:
Pericarditis and CHF (congestive heart failure).
This serious,acute side effect may be fatal and could occur even with low, cumulative doxorubicin doses.
Chronic cardiotoxicity occurs due to cumulative myocardial damage.8
Myocyte pathology involves both myofiber disruption and cytoplasmic reticulum dilation.
In latter stages, a "diffuse myocardial fibrosis" may be observed.
This pathology is likely unique to anthracycline anticancer agents allowing for differential diagnosis (versus ischemic myocardial damage or viral cardiomyopathy).
Anthracycline-caused cardiotoxicity often presents with typical CHF symptoms such as:
Peripheral edema and in some more severe cases,
Pulmonary edema(severe cases).
Risk factors for anthracycline-caused cardiotoxicity include:
Concurrent or previous chest radiation
CHF associated with doxorubicin administration is often treatable using usual CHF therapies, such as diuresis.8
An iron-chelating agent, dexrazoxane (Totect, Zinecard) is an FDA approved drug which may prevent or decrease anthracycline related cardiotoxicity in women with metastatic breast cancer and who have received doxorubicin at a cumulative dose of 300 mg/m2.3
Dexrazoxane is a catalytic topoisomerase II inhibitor which both in animal models and in randomized controlled clinical trials appear to substantially and dramatically decrease cardiac toxicity in breast cancer patients.8
Patients receiving dexrazoxane show notably reduced decreases in left ventricular ejection fraction at each doxorubicin dosage.
Furthermore, direct histological analysis of cardiac biopsies support reduced pathological change.
Effects of dexrazoxane on antitumor activity remains to be fully elucidated; however, this agent is not recommended for use at time of initiation of doxorubicin treatment.8
Another late-onset doxorubicin (as well as other anthracyclines) toxicity is secondary leukemia.
The side effect is likely due to balanced chromosomal translocations due to topoisomerase II "poisoning."
The risk level of secondary acute myeloid leukemia (AML) is about 2% or less.
In those clinical settings in which the likelihood of cure is high, the risk of a secondary leukemia is and especially important consideration, such as in the pediatric setting or in anthracycline drug administration as adjuvant treatment for breast cancer.7,8
Doxorubicin has been US FDA approved for certain clinical indications associated with these tumor types:
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Transitional cell bladder cancer