Chapter 23 topoisomerase inhibitors

TOPOISOMERASE INTERACTING
AGENTS

• Topoisomerases are ubiquitous and essential for all organisms
as they prevent and resolve DNA and RNA entanglements and
resolve DNA supercoiling during transcription and replication.
Topoisomerase I Topoisomerase II

• Type I Topoisomerase enzymes binds to a DNA molecule, it cuts one
strand, simultaneously generating a covalent phosphoester bond
between the released 5′ phosphate on the DNA & a tyrosine residue in
the enzyme.
• Formation of phosphotyrosine bond does not require ATP or another
source of energy.
• The free 3′-hydroxyl end of the DNA is held noncovalently by the
enzyme.
• The DNA strand that has not been cleaved is then passed through the
single-stranded break. The cleaved strand is then resealed & thus
removes negative supercoils.

TOPOISOMERSE INTERACTING AGENTS
Topoisomerase I Inhibitor:
• CAMPTOTHECINS: - Irinotecan
- Topotecan

CAMPTOTHECINS
Mechanism of Action:
• Camptothecins are called topoisomerase "poisons “
• Kill cells not by inhibiting topoisomerase catalysis, but by
stabilizing the normally transient reaction intermediate in
which the enzyme (Top1) is covalently linked to DNA.

• Addition of camptothecin
results in the formation of the
ternary complex (Drug-Top1-
DNA) & prevents relegation of
DNA
• These lesions are reversible and
disappear with removal of the
drug
• Collision between advancing
replication fork with the ternary
complex leads to DNA damage
and cell death.
• This may also account for S
phase specificity of cell cycle of
camptothecin cell toxicity.

Mechanism Of Resistance:
• Decreases Expression of top I
• Mutation in top I enzyme with decreased affinity for the drug.
• Increased expression of multidrug resistance phenotype with
over expression of P glycoprotein. Results in enhanced efflux
of drug and decreased intracellular accumulation of drug
• Decreased formation of the cytoxic metabolite SN 38 through
decreased activity and /or expression of carboxylesterase
enzyme.

IRINOTECAN
• It is a prodrug
• Active metabolite : SN-38
Pharmacokinetic:
• 50 % protein bound, SN-38 shows extensive protein binding : 95
%
• Half life (t1/2) irinotecan : 6-12 hrs, SN-38: 10-20 hrs
• Renal excretion accounts for 25 % of administered dose
• Remaining is eliminated by hepatic metabolism and biliary
excretion
DOSE :
• Administered intravenously as a weekly infusion of 125 mg/m2
for 4 weeks with a 2 -week rest period or, alternatively, 240 to 350
mg/m2 every 3 weeks

USES :
1. Stage IV or relapsed colorectal cancer

2. Small Cell Lung Cancer
- Cisplatin/ Carboplatin + Irinotecane combination in extensive
stage
3. Non small cell lung cancer
4. Locally Advanced or Metastatic Gastric cancer
- FOLFIRI regimen as first line therapy
- Irinotecane as single agent (preffered) or in combination with
other cytotoxic drugs (cisplatin or docetaxel or Capcetabine)
are used in second line or third line settings.
5. Recurrent or Metastatic Cervical cancer : Second line therapy

Side effects :
 Myelosupression
 Diarrhea : two mechanism :
1. Acute Cholinergic Effects (< 24 hrs)
----- treatment : ATROPIN (0.25- 1mg I/V)
2. Mucosal Cytoxicity : ( > 24 hrs)
----- treatment : LOPERAMIDE (4mg P/O as loading dose  2
mg every 2 hrs  can be stopped if pt. is diarrhoea free for 12 hrs)
• SN- 38 is glucuronidated in the liver by UGT 1 A 1 , and
deficiencies in this pathway may increase the risk of diarrhea and
myelosuppression
 Nausea, vomiting, Mild Alopecia
Dose adjustment is recommended for:
Patients who are homozygous for UGT1A1 * 28 allele
Hepatic dysfunction

TOPOTECAN
Pharmacokinetics:
• 30 % protein bound
• 40% oral bioavailability;
• Topotecan penetration into the CNS is greater than that of
other camptothecins, CSF drug levels reach 30 % of plasma
levels
• T1/2 : 2-3 h (IV) or 3-6 h (oral)
• Renal excretion is the major route of elimination of the drug
and its metabolites
Dose Adjustment:
• 50 % dose reduction is recommended for patients with mild
renal impairment (creatinine clearance 40 to 60 mL/min).
• Renal Dysfunction

Uses
• Metastatic ovarian cancer
• Cervical cancer (Stage IV B, recurrent disease)
• Small cell lung cancer
• Non-small cell lung cancer
• AML, MDS
Dose :
• Administered intravenously at a dose of 1.5 mg/m2 as a 30-
minute infusion daily for 5 days, followed by a 2-week period
of rest

Side effects:
• Myelosuppression M/C (especially neutropenia)
• Thrombocytopenia and moderate to sever anaemia are less
common
• Nausea , vomiting, Diarrhoea , Low grade fever, fatigue,
alopecia, skin rash---- Milder toxicities
• Microscopic Hematuria (< 10 %)

New formulations of Camptothecin
• New formulations of camptothecin conjugates and analogs are
currently in clinical development in an effort to improve the
therapeutic index

Topoisomerase II Inhibitor :
• ANTHRACYCLINS : - Doxorubicin
- Liposomal Doxoruibicin
- Daunorubicin
- Epirubicin
- Idarubicin
• ANTHRACENEDIONES : - Mitoxantrone
• DACTINOMYCIN
• EPIPODOPHYLLOTOXINS : - Etoposide
- Teniposide
DNA
Intercalaters
Non-
Intercalaters

• Type II topoisomerase enzymes function as homo- or
heterodimers and require ATP for catalysis.
• 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.
• In this state the protein dimer is stabilized, forming a gate in the
DNA through which a second DNA double-helix strand can
pass in an energy-dependent fashion and finally broken DNA is
• relegated
DNA is unable to
relegate,leading to
double-strand DNA
breaks & cell death

ANTHRACYCLINS
• Anthracyclines are natural products derived from Streptomyces
peucetius variation caesius
MOA :
• Intercalation in the DNA: The drugs insert nonspecifically
between adjacent base pairs and bind to the sugar-phosphate
backbone of DNA. This causes local uncoiling and, thus, blocks
DNA and RNA synthesis
• Inhibits transcription: Inhibits topo II by forming a cleavable
complex with DNA and topII. Creates uncompensated DNA helix
torsional tension, leading to eventual DNA breaks.
• The quinone structure of anthracyclines enhances the catalysis of
oxidation-reduction reactions, thereby promoting the generation of
oxygen free radicals, which may be involved in antitumor effects
as well as toxicity associated with these drugs.

Mechanism of Resistance
• Increased expression of the multidrug resistance gene with
elevated P glycoprotein levels, which leads to incresed drug
efflux and decreased intracellular drug accumulation
• Decrease expression of top II
• Mutation in top II with decrease binding affinity for
doxorubicin
• Increase expression of sulfhydryl proteins, including
glutathione and glutathione dependent protein

Doxorubicin & liposomal Doxorubicin
• Doxorubicin differs from daunorubicin
by a single hydroxyl group at C 14
• Doxorubicin is also available in a polyethylene glycol
(PEG)ylated liposomal form--Liposomal Doxorubicin
• Protected from chemical and enzymatic degradation, reduced
plasma protein binding, and decreased uptake in normal
tissues.
• Penetrates tumour tissue in to which doxorubicin is released.

Pharmacokinetic :
• 75 % of doxorubicin and its metabolites are bound to plasma
protien. Half life T1/2: 20 to 48 hrs
• Metabolized in the liver to active hydroxylated metabolite
doxorubicinol and 40-50 % of drug eliminated via bile excretion
in feces.
• Urinary excretion of doxorubicin and other anthracyclines is low,
comprising less than 10 % of the administered dose.
Dose Adjustment :
• Doxorubicin dose may be reduced by 50 % for plasma bilirubin
concentrations ranging from 1.2 to 3.0 mg/dL, by 75 % for values
of 3.1 to 5.0 mg/dL, and withheld for values greater than 5
mg/dL.

USES : Breast Cancer
Adjuvant CT Regimen in Her2 Negative Disease
All regimens are Cat 1

Adjuvant CT Regimen in Her2 Positive Disease

USES REGIMENS
Hodgkins Lymphoma ABVD (M/C)
BEACOPP, Escalated BEACOPP
Standford V
Non Hodgkins Lymphoma (DLBCL) R- CHOP (Rituximab,
Cyclophosphamide,
Hydroxyldaunrubicin i.e doxorubicin,
Vincristin , Prednisone)
Ewings Sarcoma Localized disease : VAC/ IE (Vincrist,
Doxo, Cyclo alternating with ifosfamide,
Etoposide)
Metastatic : VAdriaC
Osteosarcoma (first line therapy for
primary / Neoadjuvant/ Adjuvant /
Metastatic)
Cisplatin and Doxorubicin
MAP (high dose Mtx, doxorubicin,
cisplatin)
MAP + ifosfamide
Muscle invasive bladder cancer
(neoadjuvant/ adjuvant)
Metastatic bladder cancer
ddMVAC (Mtx, Vinblastin, Doxorubicin,
Cisplatin) with Growth factor support

Other uses : ALL, AML, CLL,
Non small cell lung cancer
NHL, Mantle Cell Lymphoma, Mycosis
fungoides ,
Gastric Ca., Thyroid Ca.
Nephroblastoma, Neuroblastoma, Wilms
Tumour
Recurrent ovarian cancer (After Failure
of platinum based chemotherapy)
Carboplatin + Liposomal Doxorubicin
(CAT 1)
Advance Kaposis Sarcoma Liposomal Doxorubicin (Response rate
51-76 %)
Multiple Myeloma Liposomal Doxorubicin in combination
with Bortezomib

• DOSE:
- Doxorubicin : 30 to 75 mg/m2 every 3 weeks intravenously
- Liposomal Doxorubicin : 20 to 60 mg/m2 every 3 weeks
intravenously

SIDE EFFECTS:
• Myeosuppresion
• Mucositis
• Alopecia (usually reversible in 3mths after termination of treatment)
• Nausea & vomiting
• Diarrhea
• Potent vesicant : Extravasation can lead to sever necrosis of skin
and local tissues
(Longer infusions are recommended by Central Venous Catheter)
Acute Treatment : Ice & dimethyl sulfoxide
Extensive treatment : Surgical debridemnt and skin grafts (sever
cases)
• Flare reaction ( erythema) at infusion site
• Red orange discolouration of urine, Hyperpigmentation of nails
• Radiation Recall (inflammatory reaction at sites of previous
radiation and can lead to pericarditis, Pleural effusion, skin rash)
• Secondary Leukemia
• Cardiac toxicity

Liposomal Doxorubicin:
Side effects
• Associated with less nausea / vomiting and mild
myelosuppression.
• Hand-foot syndrome
• Acute infusion reaction manifested by flushing, dyspnea,
edema, fever, chills, rash, bronchospasm and hypertension

DAUNARUBICIN
• Daunorubicin is similar in structure doxorubicin
• More lipid soluble then doxorubicin
Pharmacokinetic:
• Extensively binds to plasma protein (60 -70 %)
• Metabolized in liver and also undergoes substantial
elimination by the kidneys .
• Half life (t1/2) : 18.5 hrs
• Dose reduction for hepatic and renal dysfunction is
recommended

Uses
• FDA approved : ALL and AML.
Also used in Ewing's sarcoma,
nephroblastoma,
CML, NHL.
• Dose : administered intravenously 30 to 45 mg/m2 on 3
consecutive days in combination chemotherapy .
Side effects:
• Myelosuppression,
• Nausea, vomiting, diarrohea
• Mucositis, Alopecia (usually reversible within 5-7 weeks after
termination of treatment)
• Cardiac toxicity (Cummulative dose of > 550 mg/ m2)
• Strong Vesicant

EPIRUBICIN
DOSE : 60 to 120 mg/m2 every 3 to 4 weeks given intravenously
(Incidence of N/V ,
alopecia, cardiac toxicity
is less with epirubicin
compared to doxorubicin)

Idarubicin
• Idarubicin is a synthetic derivative of daunorubicin, lacking
the 4-methoxy group .
• Uses : AML , ALL
• DOSE : 12 mg/m2 given I/V for 3 consecutive days .
• Idarubicin has similar toxicities as daunorubicin, including
myelosuppression, nausea, vomiting, alopecia, cardiac toxicity,
and tissue necrosis in cases of extravasation
• 50 % dose reductions are recommended for Sr bilirubin of 2.6
to 5 mg/dL and it should not be given if the bilirubin is greater
than 5 mg/dL.

CARDIAC TOXICITY
Acute cardiotoxicity:
• Reversible
• Develops during or within days of anthracycline infusion
• Clinical signs include tachycardia, hypotension,
electrocardiogram changes, and arrhythmias-  may result in
transient congestive heart failure ( CHF)
• Incidence of which has been significantly reduced by slowing
doxorubicin infusion rates.
• It is rarely a fatal

Chronic cardiotoxicity :
• It is the most common type of anthracycline damage and is
irreversible.
• Dose dependent
• Peaks at 1 to 3 months but can occur even years after therapy.
• Clinical signs include fatigue, dyspnea on exertion, orthopnea,
sinus tachycardia, S3 gallop rhythm, pedal edema/pleural
effusions, and elevated jugular venous distention …. dilated
cardiomyopathy with CHF
• Fatal

Mechanism of Anthracycline Cardiotoxicity
• The production of free radicals generated during
cardiomyocyte anthracycline metabolism results in membrane
lipid peroxidation, with the consequent activation of the
extrinsic and intrinsic apoptotic pathways.
• Free radicals are generated by enzymatic reduction of the
anthracycline quinone ring and by formation of iron
anthracycline complexes .
• The intrinsic antioxidant defense of the cardiomyocyte is more
limited than other organs, leading to its apparent selective
toxicity profile.

Incidence of anthracycline cardiomyopathy depends on
• Cumulative dose:
Cummulative dose Incidence of
Cardiotoxicity
Doxorubicin : 400 -450 mg / m2
Daunarubicin : 900 mg/m2
Epirubicin : 800 -935 mg/ m2
Idarubicn : 223 mg / m2
5 %

Predisposition to cardiac damage includes
• Previous H/O coronary artery disease, other valvular or
myocardial conditions, and hypertension
• Mediastinal irradiation
• Older ( > 70 years) or younger ( < 4years ) age,
• Prior use of anthracyclins or other cardiac toxins
• Co administration of other chemotherapy agent (eg Paclitaxel ,
cyclophosphamide)
• Concurrent trastuzumab appears to potentiate anthracycline
cardiotoxicity

• Sequential administration of paclitaxel  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
• Doses of epirubicin below 1,000 mg/m2 and daunorubicin
below 550 mg/m2 are considered safe.
• Liposomal doxorubicin is associated with less cardiac toxicity.
• In pediatrics, it is important to be aware that conduction
disturbances ( second-degree atrioventricular block) and
arrhythmias ( both supraventricular and ventricular) may be
detected during therapy, but have no known acute/chronic
consequence.

Monitoring of Cardiac function during treatment:
 Electrocardiography
(Include sinus tachycardia, low voltage, poor R wave progression,
and nonspecific T wave changes )
 Serial non invasive monitoring of LVEF:
A. Echocardiography :
Left ventricular diastolic dysfunction  left ventricular systolic
dysfunction, particularly affecting the septal motion. With full
development of cardiomyopathy, there is global hypokinesis and
muscle wall thinning.
B. Radionuclide scans. (MUGA Scan)
 Biomarkers:
• Sr cardiac troponin T levels : measure of active myocardial
myocyte necrosis
• Brain natriuretic peptide levels : peptide synthesized in the
ventricles correlate with degree of heart failure

 Percutaneous Endomyocardial biopsy (Rare):
• 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

• Numerous studies demonstrate the danger of embarking on
anthracycline therapy in patients with underlying cardiac
disease (e.g., a baseline LVEF of less than 50 % ) and of
continuing therapy after a documented decrease in ejection
fraction by more than 10 % ( if this decrease falls below the
lower limit of normal ) .
• A low LVEF is a contraindication for anthracycline therapy

• Schwartz et al. have developed a monitoring algorithm with
scheduled frequent ejection fraction measurements, that, when
used, has demonstrated a four-fold reduction in the risk of
congestive heart failure
Schwartz et al Am J Med 1987; 82:1109.
High Risk : known heart disease, ECG
Abnormalities, RT, Cyclophosmaide therapy
or EF < 40 %

• In a small prospective study, Nousiainen et al. reported that it
was possible to distinguish patients likely to develop
cardiactoxicity from others by LVEF measures at baseline and
at 200 mg/m2 doxorubicin.
• A fall of 10 % or more at this low cumulative dose had 72 %
specificity and 90% sensitivity in detecting later cardiotoxicity

Prevention of Cardiotoxicity
 Altering Infusional Protocol
• When doxorubicin is given by a low-dose weekly regimen ( 10
to 20 mg/m2/wk) or by slow continuous infusion over 96
hours, cumulative doses of more than 500 mg/m2 can be given
 Alternate anthracycline derivatives
 Liposomal analogoues ( liposomal Doxorubicin)
 Angiotensin-converting enzyme inhibitors, β -blockers, statins
and diuretics are used

Dexrazoxane
• Dexrazoxane is FDA approved to prevent anthracycline
induced cardiotoxicity in women with metastatic breast cancer
who have received a total cumulative dose of doxorubicin of
300 mg/m2 & would benefit from continued treatment.
• MOA : Dexrazoxane chelates iron and copper, thereby
interfering with the redox reactions that generate free radicals
and damage myocardial lipids
• Recommended dose is to give dexrazoxane I.V. 30 minutes
before doxorubicin at a ratio of dex:dox of 10:1

MITOXANTRONE
• Mitoxantrone is the only clinically approved anthracenedione.
MOA :
• DNA intercalator and stabilizes the Top2- DNA complex, leading
to double-strand DNA breaks
• Relative to anthracyclines, mitoxantrone is less likely to undergo
oxidation-reduction reactions and form free radicals, thereby
decreasing its cardiac toxicity.
Pharmacokinetic:
• Extensively bound to plasma protein (78 %)
• Metabolized in liver by microsomal P450 system
• Elimination is mainly by H-B route , 25 % is excreted in feces
• Renal clearance 10 %
• Half life (t1/2 ) : 75 hrs (median)

USES :
• Advanced, Hormone refractory prostate cancer (used in
combination with pednisone as initial therapy)
• AML
• ALL
• Metastatic breast cancer
• Liver cancer
• NHL

Toxicities:
• Myelosuppression
• Nausea,vomiting, alopecia, and mucositis are less common
compared to doxorubicin.
• Cardiac toxicity is generally seen at cumulative doses greater
than 160 mg/m2
• Vesicant
• Blue discolouration of fingernails ,sclera and urine (for 1-2 days
after treatment)
• Use with caution in pts with abnormal LFT (dose modification
should be considered)

Dactinomycin
• Actinomycins were the first anticancer antibiotics isolated
from Streptomyces
• The derivative presently in use is dactinomycin.
• Structurally, dactinomycin is a "chromopeptide," consisting of
a planar phenoxazone ring (which produces the yellow-red
color of the drug), attached to two peptide side chains .
• MOA : Dactinomycin can intercalate into DNA between
adjacent guanine-cytosine bases, thereby poisoning Top2 and
leading to lethal double-strand DNA breaks.

Mechanism of resistance :
• Increased expression of the multidrug resistant gene with
elevated P-glycoprotein levels leads to increase drug efflux
and decrease intracellular accumulation
Pharmacokinetic
• Clinical pharmacology not well characterized
• Metabolized only to some extent
• Most of the drug is eliminated in unchanged form by biliary
(50 %) and renal (20 %) excretion
• Half life (T1/2) : 36 hrs

USES:
• Wilms tumour
• Rhabdomyosarcoma
• Ewings Sarcoma
• Gestational trophoblastic disease
• Germ cell tumour

Side Effetcs :
• Myelosuppression,
• Nausea, vomiting,
• Alopecia,
• Erythema, and acne.
• Radiation recall
• Veno-occlusive disease of the liver
• Severe tissue necrosis in cases of extravasation.

EPIPODOPHYLLOTOXIN: ETOPOSIDE
• Glycoside derivatives of podophyllotoxin, an antimicrotubule
agent extracted from the mandrake plant
• Primarily function as Top2 poisons rather than through
antimicrotubule mechanisms
MOA :
• Inhibits Top II by stabilizing the Top II DNA complex and
preventing unwinding of DNA
• Cell cycle specific agent with activity in late S and G2 phase

Mechanism of resistance :
• Increased expression of the multidrug resistance gene with
elevated P glycoprotein levels, which leads to increased drug
efflux and decreased intracellular drug accumulation
• Decrease expression of top II
• Mutation in top II with decrease binding affinity to drug
• Enhanced activity of DNA repair enzyme

Pharmacokinetic:
• 90 – 95% is protein bound mainly to albumin
• 25-75 % Bioavailability (I/V)
• Half life t1/2 : 3-12 hrs
• Majority of etoposide is cleared unchanged by the kidneys
(40-60 %)
• 25 % dose reduction is recommended in patients with a
creatinine clearance of 15 to 50 mL/min. And 50 % in
patients with a creatinine clearance less than 15 mL/min.

Etoposide
• USES
• Small cell carcinoma
• Testicular carcinoma
USES Regimens
Small Cell Lung Carcinoma
Testicular Cancer (First line
therapy)
Metastatic testicular ca Oral Etoposide

USES Regimens
Hodgkins Lymphoma BEACOPP
Escalated BEACOPP
Stanford V
Ewings Sarcoma (Local / metastatic) VAC/IE (Vincristine, Doxorubicin,
Cyclophosphamide alternating with
ifosfamide, Etoposide)
VIDE
Osteosarcoma : Second line (relapsed/
refractory/ metastatic )
Etoposide in combination with
cyclophosphamide/ Ifosfamide and
other cytotoxic drugs
Other uses includes :
ALL, AML
NHL, Primary cutaneous T cell
Lymphoma
Myelodysplastic syndrome
Multiple Myeloma
Endometrial, Ovarian germ cell tumour,
Gestational Trophoblastic Neoplasm,
NSCLC, Retinoblastoma

SIDE EFFECTS
• Myelosuppression (Thrombocytopenia is less common than
leukopenia)
• Mild to moderate nausea, vomiting, diarrhea, mucositis, and
alopecia , metallic taste during infusion of drug
• Among the Top2 poisons, epipodophyllotoxins are associated
with the greatest risk for development of secondary malignancies
 4% 6-year cumulative risk.
• Myelomonocytic (FAB M4 ) and monoblastic (FAB M5 )
variants of AML are the most common presentations of
epipodophyllotoxin-related leukemia resulting from balanced
translocations affecting the breakpoint cluster region of the MLL
gene at chromosome 11 q23

Teniposide
• Teniposide contains a thiophene group in place of the methyl
group on the glucose moiety of etoposide
USES :
• FDA approved for refractory pediatric acute lymphoid leukemia
(165 – 250 mg/ m2 weekly or twice weekly)
• Also used in adult neuroblastoma and NHL
Dose:
• Adults: ranges from 30 to 100 mg/m2 intravenously, used either
alone or in combination chemotherapy
Side Effects :
• Same as Etoposide
• Associated with greater hypersensitivty reaction
Dose adjustment for hepatic and renal dysfunction

Chapter 23 topoisomerase inhibitors

Chapter 23 topoisomerase inhibitors

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Chapter 23 topoisomerase inhibitors