1. Dr. VARUN GOEL
MEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE, DELHI

2. • In the 1950s, simultaneous efforts by French
and Italian researchers led to the
development of Daunorubicin.
• Daunorubicin was the first of the
anthracyclines developed.
• Formed by the fermentation products of
bacterium Streptomyces peucetius var.
caesius and was originally described as
antitumor antibiotic.

3. • The large and growing family of Anthracyclines
now includes over 2,000 known analogs.
• Derivatives of clinical use are:
– Daunorubicin (Cerubidine, Daunomycin, Rubidomycin
– Doxorubicin (Adriamycin, Rubex)
– Epirubicin
(Ellence, Farmorubicin(e), Farmorubicina, Pharmorubicin)
.
– Idarubicin (Idamycin, Zavedos)
– Amrubicin (Calced)
– Esorubicin
– Aclarubicin (Aclacinomycin)
– Pirarubicin.
– Valrubicin (Valstar)

4. • These compounds consist of:
– Planar Hydrophobic tetracycline ring
– Daunosamine sugar linked through a glycosidic
linkage.
• All drugs are positively charged at physiologic
pH, favoring intercalation into DNA.
• Anthracyclines possess Quinone moieties on
adjacent rings : Allow them to participate in
electron transfer reactions and generate
oxygen free radicals.

5. • Daunomycin and doxorubicin differ only by a single
hydroxyl at position C14, yet have distinct spectra of
antitumor activity.
• Idarubicin is a semisynthetic derivative of
daunomycin (4-demethoxydaunorubicin) lacking the
4-methoxy group present on the parent compound.
• Epirubicin is an epimer of doxorubicin having the C4′
hydroxyl group on the amino sugar in the equatorial
rather than the axial position. This increases
lipophilicity compared with doxorubicin.

6. • Cell cycle nonspecific (predominant action on
G2/S phase) of cell cycle.
• Various mechanisms are implicated for its
cytotoxicity:
– DNA intercalation.
– Inhibition of topoisomerase II
– Formation of cytotoxic oxygen free radical.

7. • Intracellular drug concentrated in the nucleus
• Anthracycline in the nucleus is intercalated
into the DNA double helix.
• The consensus sequence for highest
doxorubicin affinity is 5´-TCA.
• It is the planar ring, which actually
intercalates into DNA and the side chain
provides an important hydrogen-bonding
function.
• Intercalation prevents replication of rapidly
growing cancer cells

9. • DNA topoisomerases are a general class of
enzymes that alter the topology of DNA.
• Found in all organisms, including
Archaebacteria, viruses, yeast, Drosophila, and
humans.
• Access to DNA during processes such as
replication, transcription, and recombination
requires double-helical DNA to be
separated, resulting in torsional stress.
• There are two general classes of
topoisomerases; type I and type II, distinguished
by the number of DNA strand breaks they make
during catalysis.

10. • Top1 is important in supporting replication fork
movement during DNA replication and to relax
supercoils generated during transcription.
• Top2 is responsible for:
– unlinking intertwined daughter duplexes during DNA
replication
– contributes to DNA relaxation during transcription
– facilitates remodeling of chromatin structure.
• Type II topoisomerase enzymes function as
homo- or heterodimers and require adenosine
triphosphate for catalysis.

11. • A Topoisomerase dimer binds to DNA, forming a double-strand
DNA break in which the proteins are covalently bound to the 5´
end of broken DNA strands to form the Top2 cleavable complex.
• Forms a gate in the DNA through which a second DNA double-
helix strand can pass in an energy-dependent fashion.
• Anthracyclines poison Top2 by stabilizing the DNA-Top2
cleavable complexes, leading to DNA double-strand breaks

12. • Main mechanism of generating O2 Free
Radical is one-electron reduction of the
Anthracyclines’ quinone side rings.
• Catalyzed by Flavin-centered
dehydrogenases, including cytochrome P-450
reductase, NADH dehydrogenase (complex I
of the mitochondrial electron transport
chain), xanthine oxidase, and cytochrome B5
reductase.
• Cause widespread damage to intracellular
macromolecules, including lipid
membranes, DNA bases, and thiol-containing
transport proteins.

14. 02
P450 reductase

15. • Resistance to topoisomerase-targeting drugs
can involve alterations in
• drug accumulation,
• Increased expression of the multidrug –resistant(MDR)
gene with elevated P-170 levels leading to drug efflux
• Decreased expression of Topoisomerase II.
• Mutation in Topoisomerase II with decreased
binding affinity to drug.
• Increased expression of sulphydryl proteins
including glutathione reductase.

16. Drug Duanorubicin Doxorubicin Epirubicin Idarubicin
Protein 60-70% 60-70% 80% 70-80%
binding
CSF/plasma Very low Very low Very low low
ratio
T1/2: ά 40 min. 10 min 18.3hr 11.3hr
γ 20-50 hr 30 hr 21.1hr 40-60hr
Metabolism Daunorubicinol,7- Doxorubicinol Glucuronides of 13-idarubicinol
deoxyaglycone (MC), 7- parent compd.
deoxyaglycone
Excretion Biliary (70%), Biliary (50%), Renal Biliary (60-70%), 80% renal
Renal(<20%) (<10%) renal (20%)
Toxicity Myelosuppression,muc Myelosuppression, Leukopenia Leukopenia
ositis, aloplecia,cardiac mucositis, Thrombocytopenia Thrombocytopenia
toxicity, vesicant aloplecia,cardiac , ,
toxicity, vesicant cardiotoxicity(=do cardiotoxicity(<do
xorubicin) xorubicin)
Route of Intravenous (i.v.) i.v. i.v. i.v., oral(30%)
administratio
n

17. Drug FDA Indication Usual Dose Dose Adjustments
Doxorubicin ALL 40-60 mg/m2 every 3-4 weeks Hepatic dysfunction
AML or
CLL 60-75 mg/m2 every 3 weeks
Kaposi's sarcoma, Non-Hodgkin's
lymphoma, Mantle cell lymphoma
Mycosis fungoides, Hodgkin's
lymphoma, Gastric, Ewing's sarcoma
Prostate, Thyroid
Nephroblastoma
Neuroblastoma
Non-small cell lung
Ovarian
Transitional cell bladder
Cervical 30 mg/m2
Langerhans' cell 50 mg on days 1 and 22 every 42 days
Multiple myeloma 9 mg/m2 continuous infusion days 1 to 4
Liposomal Kaposi's sarcoma 20 mg/m2 every 3 weeks Hepatic dysfunction
doxorubicin Ovarian 50 mg/m2 every 4 weeks
Daunorubicin ALL 30-45 mg/m2 daily for 3 days Renal or hepatic
AML dysfunction
Epirubicin Breast 100-120 mg/m2 every 3-4 weeks Hepatic or renal
or dysfunction
60 mg/m2 weekly for 2 weeks followed by 1-2
weeks rest
Idarubicin AML 10-12 mg/m2 daily for 2-3 days Hepatic or renal
dysfunction

18.  Amrubicin, a fully synthetic 9-amino
anthracycline, is approved and marketed in
Japan for the treatment of lung cancer. A
recent randomized phase 2 study found
that amrubicin was superior to topotecan in
60 relapsed small cell lung cancer patients
in terms of response rates.
 Additional anthracyclines are in clinical
development including aclarubicin,
valrubicin, and zorubicin. All appear to
share a similar mechanism of action in
terms of topoisomerase 2 poisoning.

19. Duanorubicin Doxorubicin Epirubicin Idarubicin
Dexa, 5-FU , Dexa, 5-FU , Heparin : Heparin :
Heparin : Heparin : concurrent use concurrent use
concurrent use concurrent use precipitate precipitate
precipitate precipitate formation. formation.
formation. formation.
Cyclophosphamide: Cyclophosphamide: Probenecid : ↑
H’ghic ↑myelosuppression risk of uric acid
cystitis, Cardiotoxic nephropathy
ity
Phenytoin, gardenal Cimetidine ↓ AUC
: ↑clearance by 50%
Digoxin : decreases
bioavail.
6-MP:
↑hepatotoxicity

21. • Common side effect in all Anthracyclines.
• Special considerations are necessary
• Chronic cardiotoxicity is the most common type
of anthracycline damage.
• The prevalence of late subclinical cardiac damage
has been reported to be more than 57% at a
median of 6.4 years after treatment among
survivors of childhood cancers .
• The incidence of clinical heart failure as high as
16%, 0.9 to 4.8 years after treatment.
• Differences in study population, treatment
protocols, and duration of follow-up could
account for this wide variability
Ann Oncol
2002

22. Can be divided into:
• Acute or Subacute: Heart damage that
develops immediately after the infusion of the
drug or within a week of therapy.
• Early onset chronic progressive cardiotoxicity:
a depression of myocardial function which
occurs during the treatment or within the first
year after treatment.
• Late onset chronic progressive cardiotoxicity:
this occurs at least 1 year after the end of
treatment.
• Acute doxorubicin cardiotoxicity is reversible
but chronic is irreversible.

23. • Early Cardiotoxicity: Myocarditis-pericarditis.
• Early cardiotoxicity is presumably related to
myocyte damage or death resulting in depressed
left ventricular contractility.
• Chronic cardiotoxicity: Cardiomyopathy -
-Myofibrillar loss
-vacuolar degeneration and coalescence
of the sarcotubular system related to myocyte
damage or death resulting in depressed left
ventricular contractility & decreased left
ventricular systolic function.
• Chronic cardiotoxicity peaks at 1 to 3 months,
but can occur even years after therapy.

24.  Myocardial damage occurs by several
mechanisms, the most important is generation of
reactive oxygen species during electron transfer
from the semiquinone to quinone moieties of the
anthracycline.
 The generation of hydrogen peroxide and the
peroxidation of myocardial lipids contribute to
myocardial damage.
 Endomyocardial biopsy is characterized by a
predominant finding of multifocal areas of patchy
and interstitial fibrosis (stellate scars) and
occasional vacuolated myocardial cells (Adria cells).
 Myocyte hypertrophy and degeneration, loss of
cross-striations, and absence of myocarditis are
also characteristic of this diagnosis.

25. Other suggested cardiotoxicity mechanisms include:
 metabolism of ANT into more hydrophilic and
cardiotoxic substances, which subsequently
accumulate in cardiomyocytes
 impaired expression of various important cardiac
proteins
 disruption of cellular and mitochondrial Ca2+
homeostasis
 induction of mitochondrial DNA lesions
 disruption of mitochondrial bioenergetics
 degradation of myofilamental and cytoskeletal
proteins, including titin and dystrophin
 interference with various pro-survival kinases

26.  predisposition to cardiac damage includes a
previous history of heart
disease, hypertension, radiation to the
mediastinum, age younger than 4 years, prior use
of anthracyclines or other cardiac toxins, and
coadministration of other chemotherapy
(e.g., paclitaxel, cyclophosphamide, or
trastuzumab).
 Sequential administration of paclitaxel followed by
doxorubicin in breast cancer patients is associated
with cardiomyopathy at total doxorubicin doses
above 340 to 380 mg/m2, whereas the reverse
sequence of drug administration did not yield the
same systemic toxicities

27.  The incidence of cardiomyopathy is related to
both cumulative dose and schedule of
administration.
 Cardiac toxicity is best correlated with peak
plasma concentration of the parent drug
rather than with the AUC.
 Greater cumulative doses of doxorubicin can
be given to patients receiving low-dose
continuous infusions than to those receiving
higher-dose bolus injections every 3-4
weeks.

28. Incidence of Clinically Detectable Congestive Heart
Failure as a Function of Cumulative Doxorubicin
Dose
Cumulative Dose Incidence of Congestive
(mg/m2) Heart Failure (%)
<350 <1
550 7
600 15
700 30

29.  Clinically detectable congestive heart failure when
doxorubicin is given at doses of 40-75 mg/m2 as
a bolus injection every 3-4 weeks. But when
doxorubicin is given by a low-dose weekly regimen
(10-20 mg/m2/wk) or by slow continuous infusion
over 96 h, cumulative doses of more than 500
mg/m2 can be given.
 Doses of epirubicin below 1,000 mg/m2 and
daunorubicin below 550 mg/m2 are considered
safe.
 Doses of idarubicin below 290 mg/m2 do not
produce clinical congestive heart failure despite
changes in cardiac ejection.

30. RISK FACTORS EFFECTS
ABNORMAL CARDIAC FUNCTION INCREASE
CUMULATIVE DOSE INCREASE
AGE Children <5 yr increased risk
SEX FEMALE SEX INCREASED RISK
IRRADIATION INCREASE
ADDITIONAL TREATMENT Co T/t WITH
CYCLO/PACLITAXEL/TRASTUZUMA
B/BLEOMYCIN
BLACK RACE INCREASE
TRISOMY21 INCREASE
LENGTH OF FOLLOW UP INCREASE
LENGTH OF INFUSION DECREASE

31.  Efforts in this direction have so far focused
on:
 Dose and formulation of the anthracyclines.
 Development of safe new derivatives.
 Simultaneous treatment with protective substances
thought to interact beneficially.

32.  Liposomal formulations are said to promote
tumor concentrations of the drug while
exposing normal tissue to lower, at best non
toxic levels.
 They are also associated with higher rates of
other toxic effects such as neutropenia
 Furthermore, these formulations are
extremely expensive and so far lack evidence
on long term safety or harms.

33. Newer anthracyclines
• tumor activated anthracycline "prodrugs”
such as pirarubicin and valrubicin and N-L-
leucyl-doxorubicin.
• unable to penetrate healthy cells, but are
activated and potentiated extracellularly by
tumor secreted peptidases.
• Disaccharide derivatives of anthracyclines are
known as third generation anthracyclines.
The best known is sabarubicin or MEN
10755.(PH 2 trials)

34.  The iron chelating agent dexrazoxane, reduce
anthracycline induced oxygen radical
production.
• Dexrazoxane(dex) is FDA approved to prevent
anthracycline induced cardiotoxicity in
women with metastatic breast cancer who
have received a total cumulative dose of
doxorubicin(dox) of 300 mg/m2 & would
benefit from continued treatment.
• Recommended dose is to give dexrazoxane
I.V. 30 minutes before doxorubicin at a ratio
of dex:dox of 10:1.

35. • include the use of
– angiotensin-converting enzyme (ACE) inhibitors
– angiotensin II receptor blockers (ARBs)
– carvedilol - has potent antioxidant and anti-
apoptotic properties.

36. • Important dose limiting toxicity .
• Leucopenia more common than
thrombocytopenia and anemia.
• Myelosuppression begins in 7 days following
administration.
• Nadir occurs by day 10-14 followed by recovery
by day 21.
• Thrombocytopenia and anemia less severe.
• Daunorubicin : BM suppression > mucositis
• Doxorubicin :BM suppression= mucositis.
• Growth factor support often needed .
• With weekly dosing or continuous infusion,
mucositis frequently becomes the dose-limiting
toxicity.

37. • Extravasation of most anthracyclines leads to
severe local injury that can continue to progress
over weeks to months.
• The drug has been shown to bind locally to
tissues
• Local wound care to prevent infection is most
important.
• A wide range of treatments including ice, steroids,
vitamin E, DMSO(dimethyl sulphoxide), and
bicarbonate used.
• Recently cardioprotectant Dexrazoxane has been
used to treat acute Anthracycline extravasations in
combination with subcutaneous granulocyte-
macrophage colony-stimulating factor to promote
wound healing.

38.  Nausea & vomiting.
 Hyperpigmentation of nails , urticaria.
 Aloplecia
 Red orange color of urine . Lasts 1-2 days
after drug administration.
 Erythema at injection site – flare reaction.
 RADIATION RECALL. increased inflammation
in previously irradiated areas can lead to
pericarditis, pleuritis and skin rashes.

39. • RISK OF SECONDARY MALIGNANCY:
• Anthracyclines are also known to multiply the
risk of developing acute myelogenous
leukemia, a form of leukemia which is usually
unresponsive to treatment and carries a poor
prognosis.
• Overall absolute risk remains low (estimated
at less than 2% at ten years after treatment)
JCO 2002