ANTIMETABOLITES

TOPOISOMERASE
INHIBITORS
ANTIMICROTUBUL
E AGENTS

D R VA R U N T N
4/16/25 2
4/16/25 3
ANTIMETABOLITES

Folate Pyrimidine Purine Adenosine

antagonist antagonist antagonist Deaminase
s s s inhibitors

4/16/25 4
 1st generation drugs -
Aminopterin, Amithopterin
(MTx)
- Newer multi-targeted
agents – Pemetrexed,
Pralatrexate
- Novel agents -
trimetrexate, piritrexim,

4/16/25 5
 Sidney Farber- Father of
Modern Chemotherapy

•
1948 - Farber used the 1st folate
analogue (aminopterin and then
amithopterin), in collaboration
with Harriet
Kilte and Yellapragada
Subbarao
•
When administered to children
with ALL in 1948, these agents
became the first drugs to induce
remission in children with ALL

4/16/25 6
4/16/25 7
METHOTREX ONCOLOGIC INDICATIONS

Breast cancer
ATE Head and neck cancer

Osteosarcoma

Acute lymphoblastic leukemia

Non-Hodgkin’s lymphoma

Primary CNS lymphoma

Meningeal leukemia and

carcinomatous meningitis

Bladder cancer

Gestational trophoblastic cancer

4/16/25 8
TOXICITY

01 02 03 04 05 06
Bone Emesis Nephrotoxi Mucositis Hepatotoxi Dermatolog
Marrow city and city ic Effects
Suppressio diarrhea
n

4/16/25 9
LEUCOVORIN RESCUE
•
Goldin developed the rescuing normal cells from toxicity by giving reduced folates to bypass the
metabolic block induced by MTX

•
24 to 36 hrs after administration of MTX was able to prevent MTX-induced host toxicity without
diminishing antitumor activity
•

4/16/25 10
Pemetrexe
Newer multi-target antifolate
d

In combination with platinum

agents in locally advanced or
metastatic Mesothelioma

In combination with platinum

agents in locally advanced or
metastatic non-squamous
NSCLC
4/16/25 11
Pralatrexa The newest folate analog
te approved for clinical use

30-40 times more potent than

MTx

For relapsed or refractory

peripheral T-cell lymphoma
(PTCL).

4/16/25 12
PURINE ANTAGONISTS
• Guanine Analogs
• Azathioprine • Endogenous purine nucleosides are involved in essential
cellular processes such as DNA and RNA synthesis, cell
• 6-mercaptopurine (6-MP)
signaling, enzyme regulation and metabolism
• 6-thioguanine (6-TG)

• They are synthetic, chemically modified analogs – mimic

• Adenine analogs the physiological molecules and exploit cellular
• Fludarabine metabolism.
• Cladiribine
• Clofarabine

4/16/25 13
4/16/25 14
PYRAMIDINE ANALOGS

4/16/25 15
 5-FLUOROURACIL
●
Fluoropyrimidine synthesized by Dr. Charles
Heidelberger in 1957
●
Antimetabolite
●
Cell cycle specific, “S” phase
●
Enters the cell by facilitated uracil transport
system
 EFFECT ON DNA
● Enters cells via uracil transport mechanism

● Anabolised to cytotoxic nucleotide forms

● Incorporation into DNA

● Inhibition of DNA synthesis and function

 EFFECT ON RNA
●
Incorporation into RNA

●
Alterations in RNA processing and mRNA
translation
o
Inhibition of TS

o
Depletion of Deoxythymidine triphosphate

o
Interfering with DNA biosynthesis and repair.
 Variations in DPYD can lead to DPD insufficiency. This results in an
inability to inactivate 5-FU leading to increased levels of active
drug - greater toxicity

•
Lower levels of the TS enzyme can lead to
−
Increased levels of active 5-FU: greater Toxicity
 DIHYDORPRIMIDINE DEHDROGENASE
● Liver expresses maximum amount of DPD, but
expressed in GIT and lymphocytes
● 85% of 5FU is metabolized
● Deficiency
○ Autosomal Recessive inheritence
○ 3-5% of population
○ Either partial or complete, may experience life-
threatening or fatal toxicity when treated with
fluoropyrimidine-based chemotherapy
○ Several molecular defects, including point mutations and
deletions due to exon skipping, have been identified in
DPD-deficient patients
USES
Broad range of solid tumors including
●
GIT
●
Breast
●
Head & Neck
●
Ovarian carcinomas
●
Back bone for colorectal regimens
●
Topical- actinic or solar Keratosis and superficial basal cell
carcinomas
LEUCOVORI Stable ternary complex
N is critical for drug
sensitivity.
More binding to
Thymidylate synthase

Endogenous reduced
folate concentration is
insufficient
●
Leucovorin expands the intracellular reduced
folate pool and permit maximal ternary
complex formation
○
Increases cytotoxicity of 5FU in time and
concentration dependant manner

●
However
○
Tolerated dose of 5FU becomes less
○
Increase GI toxicity
F-UMP TS
+ Increased inhibition

F-UMP F-UMP

TS TS
+
LV

LV
Stable ternary
 MYELOSUPPRESSION
● Dose-limiting for the bolus or weekly
schedules, less frequently observed with
infusional therapy. Neutropenia and
thrombocytopenia more common than
anemia.
○ : 21-28 days
HAND – FOOT SYNDROME (PALMAR PLANTAR
ERYTHRODYSESTHESIA)

●
Starts 5-6 weeks after treatment
○
Characterized by tingling, numbness, pain, erythema,
dryness, rash, swelling, increased pigmentation,nail
changes, pruritus of the hands and feet, and/or
desquamation.
○
Most often observed with infusional therapy and can
be dose-limiting
○
Vitamin B6 , Celecoxib, bland and mild moisturizer
 OTHERS
● Mucositis and diarrhoea

● Neurological toxicity

● Cardiac toxicity
○ Due to vasospasm

● Dermatological toxicity

● Ocular toxicity
 CAPECITABINE
● Oral 5FU prodrug

● Was first initially approved in 1998 for metastatic

breast cancer resistant to anthracyclines and
taxanes

● Rapidly and extensively metabolized by gut mucosa

● 80% bioavailability
METABOLISM

Capecitabine

Hepatic
carboxylase
Breast,
5’-deoxy-5- Colorectal,
fluorocytidine Head and neck,
Stomach,
Cytidine Cervix,
deaminase

5FU
5’-deoxy-5- Thymidine
fluorouridine phosphorylase
 USES
● Colorectal cancer
○ First line therapy for metastatic disease
○ Adjuvant to post surgery

● Breast
○ Combination with docetaxel when anthracycline
based chemotherapy has failed
○ Monotherapy as third line after paclitaxel and
anthracycline
○ Monotherapy as second line after paclitaxel is
contraindicated
 DOSAGE
●
1,250 mg/m2 PO twice daily for 2 weeks after
meal
 TOXICITY
●
Diarrhoea

●
Hand foot syndrome

●
Myelosuppresion

●
Neuropathy
 S1 COMPOUND
● Composed of three agents
○ Ftorafur
○ Chlorohydroxy dihydropyridine
○ Oxonic acid

● As an adjuvant therapy in stage 2/3 with D2

lymphadenectomy, 5 year overall survival and relapse
free survival was better than surgery alone.

● Diarrhoea has occurred in a proportion of the treated

patients
TOPOISOMERASE
INHIBITOR
S
• 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
 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 religation 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.
 IRINOTECAN
• It is a prodrug
• Active metabolite : SN-38
•
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.
5. 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
Topoisomerase II Inhibitor :
• ANTHRACYCLINS : - Doxorubicin
- Liposomal Doxoruibicin
- Daunorubicin
- Epirubicin
- Idarubicin

• ANTHRACENEDIONES : - Mitoxantrone

• DACTINOMYCIN

• EPIPODOPHYLLOTOXINS : - Etoposide
- Teniposide
• 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

•
MOA :
• 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.
•
 .
Doxorubicin & liposomal Doxorubicin
is
USES: Breast
Adjuvant
Cancer 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 ●
Cisplatin and Doxorubicin
for primary / Neoadjuvant/ ●
MAP (high dose Mtx,
Adjuvant / Metastatic) doxorubicin, cisplatin)
●
MAP + ifosfamide
●
Muscle invasive bladder ●
ddMVAC (Mtx, Vinblastin,
cancer (neoadjuvant/ Doxorubicin, Cisplatin) with Growth
adjuvant) Metastatic bladder factor support
cancer
●
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 ●
Carboplatin + Liposomal Doxorubicin
●
of platinum based chemotherapy) ●
(CAT 1)

●
Advance Kaposis Sarcoma ●
Liposomal Doxorubicin (Response rate
●
51-76 %)

●
Multiple Myeloma ●
Liposomal Doxorubicin in
combination with Bortezomib
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
 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
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.
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
 EPIPODOPHYLLOTOXIN:
ETOPOSIDE

• Glycoside derivatives of podophyllotoxin, an antimicrotubule

agent extracted from the mandrake plant
•
• Primarily function as Top2 poisons
•
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
 Etoposide
● USES ● Regimens
● Small Cell Lung Carcinoma

●
• USES
●
• Small cell carcino a
• Testicular carcino a
● 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/ ● Etoposide in combination with
● refractory/ metastatic ) 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
 Antimicrotubule agents
• These are tubulin-binding drugs that directly bind tubules,
inhibitors of tubulin-associated scaffold kinases, or
inhibitors of their associated mitotic motor proteins to,
ultimately, disrupt microtubule dynamics.

Microtubule inhibitors

Metaphase Anaphase

T h e y block mitosis in m e t a p h a s e
4/16/25 64
TAXANES

• PACLITAXEL

• DOCITAXEL

4/16/25 65
Indications:
Metastatic breast cancer

First-line treatment of locally

advanced or Metastatic NSCLC­
in combination with carboplatin.

First-line treat1nent of metastatic

pancreatic adenocarcinoma -­ in
combination with gen1citabine.
Toxicity Neuropath
y

Neutropeni
a
4/16/25 67