cytotoxic acd.pptx

CYTOTOXIC ANTICANCER DRUGS
BY- DR UTSAV SHINGHAL
JR-I
MD PHARMACOLOGY
JULY 6, 2021

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CONTENTS
• Alkylating agents
o Actions common to all alkylating agents
o Structure activity relationships
 Nitrogen mustards
 Triazenes
 Nitrosoureas
 Ethyleneimines and Methylmelamines
 Alkyl sulfonates
 Methylhydrazines
• Platinum coordination complexes

• Antimetabolites
o Folic acid analogues
o Purine and pyrimidine analogues
• Natural products
o Microtubule damaging agents
 Vinca alkaloids
 Taxanes
 Estramustine
 Epothilones

o Camptothecin analogues
o Antibiotics
o Epipodophyllotoxins
o L-asparaginase
• Common chemotherapeutic regimens

ABBREVIATIONS
• ADA: Adenosine deaminase
• Ara-C: Cytarabine (Cytosine arabinoside)
• BCNU: Carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea]
• CCNU: Lomustine [1-(2-choloroethyl)-3-cyclohexyl-1-nityrosourea]
• CNT1: Concentrative Nucleoside Transporter 1
• dCK: deoxycytidine kinase
• 5’DFCR: 5’-deoxy-5-fluoro cytidine
• dFdC: Gemcitabine (2’,2’-difluorodeoxycytidine)

• 5’DFUR: 5’-deoxy-5-fluoro uridine
• DHFR: Dihydrofolate reductase
• DTIC: Dacarbazine [5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide]
• ENT1: Equilibrative nucleoside transporter 1
• FH2 - dihydrofolate
• FH4 – tetrahydrofolate
• 5-FU: 5-Fluorouracil

• L-ASP: L-asparaginase
• methyl-CCNU: Semustine [1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea]
• MESNA: 2-Mercaptoethanesulfonate sodium
• 6-MP: 6-Mercaptopurine
• MTX-Methotrexate
• 6-TG: 6-Thioguanine
• T-IMP: Thio-inosine monophosphate

ALKYLATING AGENTS
• The discovery and initial development of alkylating anticancer drugs are based
on the observation of the effects of chemical warfare in World War I.
• The highly toxic sulfur mustard gas, used in World War I, that caused topical
burns to skin, eyes, lungs, and mucosa also caused aplasia of the bone marrow
and lymphoid tissue.
• In 1942, Louis Goodman and Alfred Gilman, demonstrated the activity of
nitrogen mustards against mouse lymphoma.
• Their clinical studies of intravenous nitrogen mustards in patients with
lymphoma launched the modern era of cancer chemotherapy.

• There are 6 major types of alkylating agents used in the chemotherapy of cancer:
Nitrogen mustards (eg. Mechlorethamine, Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan,
Bendamustine)
Triazenes (eg. Dacarbazine, Temozolomide)
Nitrosoureas (eg. Carmustine, Lomustine, Semustine, Streptozocin)
Ethyleneimines and Methylmelamines (eg. Triethylenemelamine, Altretamine, Thiotepa)
 Alkyl sulfonates (eg. Busulfan)
Methylhydrazines (eg. Procarbazine)

• All the alkylating agents form the highly reactive carbonium ion intermediates.
• These carbonium ion intermediates covalently link to sites of high electron
density, such as amine, hydroxyl, sulfhydryl and phosphate groups of DNA, RNA
and proteins.
• Their chemotherapeutic and cytotoxic effects are directly related to the alkylation
of amines, oxygen and phosphates on DNA.
• N7 of guanine is particularly susceptible to the formation of covalent bond.
• Other atoms in purine and pyrimidine bases of DNA that react with theses agents
are N1 and N3 of adenine, N3 of cytosine and O6 of guanine.
ACTIONS COMMON TO ALKYLATING DRUGS

STRUCTURE-ACTIVITY RELATIONSHIPS

NITROGEN MUSTARDS
• Mechlorethamine
N

• The second 2-chloroethyl side chain may also undergo a similar cyclization
reaction and alkylate a second guanine residue or any other nucleophilic moiety.
• This results in cross-linking of two nucleic acid chains or the linking of nucleic
acid to a protein causing a major disruption in nucleic acid function.

• Cyclophosphamide
• Ifosfamide

NOTE:
Cyclophosphamide:
• It can be orally or intravenously.
• It is activated by CYP2B6, CYP2C19, CYP2C9, CYP3A4 into 4-hydroxy
cyclophosphamide.
• 4-hydroxy cyclophosphamide and its tautomer, aldophosphamide, travel in
circulation to tumor cells where aldophosphamide cleaves spontaneously
generating phosphoramide mustard and acrolein.

• Phosphoramide mustard is responsible for anti-tumor effects, while acrolein
causes hemorrhagic cystitis.
• The selectivity of cyclophosphamide action against malignant tissues may result
in part from the capacity of normal tissues to degrade the active intermediates via
alcohol dehydrogenase, aldehyde dehydrogenase and glutathione transferase.

• The patients must receive vigorous intravenous hydration during high dose
treatment with cyclophosphamide in order to prevent cystitis. Alternatively, they
may also receive MESNA (2-Mercaptoethanesulfonate-Na+).
• If hemorrhagic cystitis has already occurred, steroids are used to treat the
condition.
• Refractory cases may even require cystectomy.
• Also, inappropriate secretion of ADH has also been observed in some patients
receiving higher doses of cyclophosphamide(>50mg/kg) and may lead to water
intoxication because these patients usually are vigorously hydrated.

• Patients receiving Ifosfamide are at even higher risk of developing hemorrhagic
cystitis.
• So, IV MESNA is given as bolus injection in a dose equal to 20% of Ifosfamide
dose concomitantly and an additional 20% again 4 and 8 hours later, for a total
MESNA dose of 60% of Ifosfamide.
• Alternatively, MESNA may be given concomitantly in a single dose equal to
Ifosfamide dose.

• Chlorambucil
• Melphalan

TRIAZENES
• Dacarbazine or DTIC
5-(3,3-dimethyl-1-triazeno)
-imidazole-4-carboxamide
• Temozolomide

NITROSOUREAS
• Carmustine or BCNU [1,3-bis-(2-chloroethyl)-1-nitrosourea]
• Lomustine or CCNU [1-(2-choloroethyl)-3-cyclohexyl-1-nityrosourea]
• Semustine or methyl-CCNU [1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-
nitrosourea]

• As with nitrogen mustards, interstrand DNA cross-linking is the primary lesion
responsible for the cytotoxicity of nitrosoureas.

ETHYLENEIMINES AND METHYLMELAMINES
• Triethylenemelamine Thiotepa
(N,N’,N’’-triethylene
thiophosphoramide)
• Altretamine
(Hexamethylmelamine)

• The precise mechanism of cytotoxicity of Altretamine is still unknown.
• But the direct relationship has been observed between the degree of
demethylation of Altretamine and its antitumor activity.
• Altretamine is N-demethylated by hepatic microsomal enzymes, producing
reactive intermediates that covalently bind to DNA, resulting in DNA damage.

ALKYL SULFONATES
• Busulfan
It also causes interstrand DNA crosslinking.

METHYLHYDRAZINES
• Procarbazine

PLATINUM COORDINATION COMPLEXES
For eg:
• Cisplatin
• Carboplatin
• Oxaliplatin

• Cisplatin and other platinum complexes donot form carbonium ion intermediates
like alkylating agents or formally alkylate DNA, rather they covalently bind to
nucleophilic sites on DNA forming intrastrand and interstrand cross-linkages.

FOLIC ACID ANALOGUES
• Methotrexate (MTX):

• Mechanism of action:
o The primary target of MTX is the enzyme Dihydrofolate reductase (DHFR).
o To function as a cofactor in one carbon transfer reaction, folate must be reduced to
tetrahydrofalate by DHFR.
o MTX has a high affinity for DHFR, cause partial depletion of N5,10 methylene FH4, N5,10
methenyl FH4 and N10 formyl FH4, cofactors that are required for the purine and
thymidylate biosynthesis.

o In addition, Methotrexate, like cellular folates undergoes addition of a series of
polyglutamates.
o These MTX polyglutamates have markedly higher inhibitory potency for additional
sites, including thymidylate synthase, the two formyl transferase reactions in purine
biosynthesis pathway.
o Also, the dihydrofolate polyglutamates accumulate in the cells due to blocked DHFR
reaction and cause inhibition of thymidylate synthase and other enzymes.

PURINE AND PYRIMIDINE ANALOGUES
• The cells may synthesize the nitrogenous bases and convert them into
nucleotides, providing substrate for DNA polymerase.
• Alternatively, cells can salvage free bases or their deoxynucleosides from the
bloodstream.
• The cells can directly take up uracil, guanine and their analogues while other
bases like adenine, cytosine and thymine and their analogues are taken up as
deoxynucleosides.

PYRIMIDINE ANALOGUES
5-Fluorouracil (5FU)
Mechanism of action:
o 5FU after entering the cell requires the enzymatic conversion into nucleotide so as to
exert its cytotoxicity.
o FUTP (5-Fluoro uridine triphosphate) gets incorporated into RNA and inhibits its
functioning.
o Alternatively, the deoxy derivative FdUMP may be produced which inhibits thymidylate
synthase and blocks the synthesis of dTTP, a necessary constituent of DNA.

o N5,10 methylene FH4, FdUMP form a covalently bound ternary complex with
thymidylate synthase and cause the sustained inhibition of thymidylate synthase due
to stability of fluoride carbon bond.
o In 5FU treated patients, FdUTP and dUTP get incorporated into DNA in place of
depleted dTTP. This calls into action the DNA excision-repair process and can lead to
the DNA strand breakage.

5-FU in combination with Leucovorin:
• Some malignant cells have an insufficient concentrations of N5,10 methylene FH4,
and thus cannot form maximal levels of the inhibited ternary complex with
thymidylate synthase and 5-Fluorodeoxyuridine monophosphate(FdUMP).
• Thus, addition of exogenous folate in the form of leucovorin increases the
formation of this complex and enhances response to 5-FU.

Capecitabine:
• It is an orally administered prodrug of 5FU.
• It is well absorbed orally.
• It is rapidly deesterified into 5’-deoxy-5-fluoro cytidine and then deaminated to
5’-deoxy-5-fluoro uridine which is further acted upon by thymidine
phosphorylase to produce 5-fluorouracil.

Cytarabine (Cytosine Arabinoside;Ara-C):
• It is an analogue of 2’-deoxycytidine, the 2’ hydroxyl group is present in a
position trans to 3’-hydroxyl group which hinders the rotation of pyrimidine
along the nucleoside base and interferes with base pairing.

• Ara-C enters the cells via ENT1 (SLC29A1) and is then phosphorylated into Ara-
CMP by deoxycytidine kinase and further into Ara-CDP and Ara-CTP by
nucleotide kinases.
• Ara-CTP then competes with dCTP for incorporation into DNA.
• The incorporated Ara-CMP is the potent inhibitor of DNA polymerase and
prevents the further elongation of nascent DNA molecule.

Azacitidine
(5-Azacytidine)
Decitabine
(2’-deoxy-5-azacytidine)

o Both Azacitidine and Decitabine enter the cell via ENT1 (SLC29A1).
o They get incorporated into the DNA, where they become covalently
bound to DNA methyl transferase, depleting intracellular enzyme.
o It leads to the global demethylation of DNA that results in tumor
differentiation and apoptosis.
o Both drugs are indicated for myelodysplasia, for which they induce the
normalization of bone marrow.

Gemcitabine
(2’,2’-difluorodeoxycytidine; dFdC)
• Gemcitabine enters the cell mainly via ENT1 and also by CNT1 and a nucleobase
transporter found in malignant mesothelioma cells..
• After entering the cell, dCK phosphorylates gemcitabine into dFdC into dFdCMP
and further into dFdCDP and dFdCTP by nucleotide kinases.

• dFdCTP competes with dCTP for incorporation into DNA.
• The incorporated dFdCMP inhibits DNA polymerase and causes DNA strand
termination.
• Also, dFdCDP inhibits ribonucleotide reductase, an enzyme responsible for the
conversion of ribonucleotides into deoxyribonucleotides. Thus, resulting in
depletion of deoxyribonucleotide pools necessary for DNA polymerase.

PURINE ANALOGUES
• 6-Mercaptopurine (6-MP):
• 6-Thioguanine (6-TG):

• Hypoxanthine guanine phosphoribosyl transferase converts 6-MP and 6-TG into
6-thioinosine monophosphate (T-IMP) and 6-thioguanosine monophosphate,
respectively.
• T-IMP is the poor substrate of guanylyl kinase and this causes intracellular
accumulation of T-IMP.
• T-IMP prevents the new formation of ribose-5-phosphate as well as conversion of
IMP into AMP and GMP.
• Also, it blocks the first committed step in the purine biosynthesis, PRPP combines
with glutamine to form 5-phospho-ß–D-ribosylamine.
• 6-TG nucleotide is incorporated into DNA, where it induces breaks in DNA.

Fludarabine phosphate:
(2-fluoro-ara-AMP)
• The drug is dephosphorylated extracellularly into the nucleoside fludarabine
which enters the cell and is rephosphorylated into active triphosphate.
• It then inhibits DNA polymerase, DNA primase, Ribonucleotide reductase and
becomes incorporated into DNA and RNA.

• Fludrabine is an effective chain terminator when incorporated into DNA.
• Incorporation of Fludrabine into RNA prevents mRNA translation.

Cladribine:
(2-chloro-2’-
deoxy adenosine)
• Cladribine after entering the cell gets phosphorylated into cladribine triphosphate,
which gets incorporated into DNA and produces DNA strand breaks.
• It is also a potent inhibitor of ribonucleotide reductase.

Clofarabine:
(2-chloro-2’-fluoro-
arabinosyl adenine)
• Clofarabine after entering the cell gets gets incorporated into DNA and
DNA strand breaks.
• It also inhibits ribonucleotide reductase.

Nelarabine:
(6-methoxy-arabinosyl-guanine)
• It is the only guanine nucleoside in clinical use.
• Nelarabine also gets incorporated into DNA and terminates DNA synthesis.

Pentostatin:
• Pentostatin is the transition state analogue of intermediate in adenosine
deaminase reaction and potently inhibits adenosine deaminase(ADA).

• Inhibition of ADA leads to intracellular accumulation of adenosine and
deoxyadenosine nucleotides, which can block the DNA synthesis by creating an
imbalance in purine nucleotide pools due to inhibition of ribonucleotide reductase.

• Deoxyadenosine also inhibits S-adenosyl homocysteine hydrolase.
• The resulting accumulation of S-adenosyl homocysteine is particularly toxic to
lymphocytes.
• Its triphosphate derivative is incorporated into DNA, resulting in strand breakage.

MICROTUBULE DAMAGING AGENTS
Vinca alkaloids:
For eg:
• Vincristine
• Vinblastine
• Eribulin

• These are cell cycle specific agents and blocks the cells in mitotic phase.
• They bind to ß-tubulin prevent their polymerization with α-tubulin protein into
microtubules.
• The mitotic spindle cannot form, duplicated chromosomes cannot align along the
division plate, and cell division arrests in metaphase.

Taxanes:
For eg:
• Paclitaxel
• Docetaxel
• Cabazitaxel

• They bind to ß-tubulin subunit on the inner surface of microtubules and
antagonize their disassembly.
• This results in the bundles of microtubules and aberrant structures derived from
microtubules appear in mitotic phase of cell cycle.
• Cell cycle arrests in mitotic phase.

Estramustine:
• It contains estradiol and normustine joined together through a carbamate link.

• Although the intent was to enhance the uptake of alkylating agent into the
estradiol sensitive prostate cancer cells.
• But Estramustine doesnot function in vivo as alkylating agent, rather, it binds to
ß-tubulin and promotes the microtubule disassembly.

Epothilones:
For eg:
Ixabepilone
• They bind to ß-tubulin site and trigger the microtubule nucleation at multiple
sites distinct from centrioles.
• This dysfunctional microtubule stabilization triggers the cell cycle arrest in G2M
interface.

CAMPTOTHECIN ANALOGUES
For eg:
• Irinotecan
• Topotecan
• The DNA topoisomerases are the nuclear enzymes that reduce torsional stress in the
supercoiled DNA.
• This allows the selected regions of DNA to become sufficiently untangled to permit
DNA replication, repair and transcription.
• There are 2 classes of topoisomerases (I and II) which meadiate DNA strand breakage
and resealing.

• Camptothecin analogues inhibit the function of topoisomerase I.
• They bind to and stabilize the normally transient DNA-topoisomerase I cleavable
complex.
• Although the initial cleavage action of topoisomerase I is not affected, the
religation step is inhibited, leading to accumulation of single strand breaks in
DNA.
• These lesions are reversible and not themselves toxic to the cell.
• However, the collision of DNA replication fork with the cleaved strand of DNA
causes an irreversible double strand DNA break, leading to death of cell.

ANTIBIOTICS
Dactinomycin:
(Actinomycin D)

• The planar phenoxazone ring intercalates between the adjacent cytosine-guanine
base pairs of DNA, while the pentapeptide lactone rings lie in the minor groove of
helix.
• It results in a Dactinomycin-DNA complex with stability sufficient to block the
transcription of DNA by RNA polymerase.
• The RNA polymerases are much more sensitive to the effects of Dactinomycin
than are the DNA polymerases.

Anthracyclines and Anthracenediones:
For eg:
• Doxorubicin
• Daunorubicin
• Idarubicin
• Epirubicin

• Anthracyclines form a heterotrimeric complex with topoisomerase II and DNA.
• DNA topoisomerase II produces double stranded breaks in DNA, allowing the
uncoiling of supercoiled DNA and then it religates the DNA strands.
• Formation of ternary complex with anthracyclines inhibits the religation of the
broken DNA strands, leading to apoptosis.

• In addition, the quinone moiety of anthracyclines can form radical intermediates
that react with oxygen to form superoxide anion, which can generate H2O2 and
OH
.
that oxidize the DNA bases, leading to apoptosis.

Bleomycin:
• Bleomycin cleaves the DNA by generating free radicals.
• The activated bleomycin generates free radicals that are responsible for
development of a 4’ radical intermediate of deoxyribose of thymidylate, causing
opening of deoxyribose ring and causing a strand break in DNA.

Mitomycin:
• Mitomycin, after intracellular enzymatic or spontaneous chemical alteration,
functions as an alkylating agent.
• It produces interstrand DNA cross linking at N6 of adenine and O6 and N7 of
guanine.

EPIPODOPHYLLOTOXINS
For eg:
• Etoposide
• Teniposide
• Like anthracyclines, they also form ternary complex with DNA and topoisomerase
II and prevent the religation of broken DNA strands leading to apoptosis.

`
L-asparaginase:
• Most normal tissues synthesize L-asparagine in an amount sufficient for protein
synthesis.
• But lymphocytic leukemias lack adequate amount of asparagine synthase and
derive the required amino acid from plasma.
• L-asparaginase by hydrolyzing the circulating L-asparagine into aspartic acid and
ammonia, deprives the malignant cells of asparagine leading to cell death.

COMMON CHEMOTHERAPEUTIC REGIMENS

COLORECTAL CANCER
• FOLFOX-6 regimen:
Lecovorin (Folinic acid): 200 mg/m2 on day 1
5-Fluorouracil: 400 mg/m2 iv bolus injection on day 1, followed by 2400-3000
mg/m2 46 hours continuous infusion on days 1 and 2
Oxaliplatin:100 mg/m2 on day1
Duration is 2 weeks upto 12 cycles can be given.

• FOLFIRI regimen:
Lecovorin (Folinic acid): 200 mg/m2 on day 1
5-Fluorouracil: 400 mg/m2 iv bolus injection on day 1, followed by 2400-3000
mg/m2 46 hours continuous infusion on days 1 and 2
Irinotecan: 180 mg/m2 on day 1
Duration of cycle is 2 weeks and upto 12 cycles.

• XELOX regimen:
Capecitabine(Xeloda): 1000 mg/m2 orally twice a day on days 1-14
Oxaliplatin: 130 mg/m2 iv infusion on day 1
Duaration of cycle is 21 days and upto 8 cycles.

• ROSWELL PARK regimen:
Leucovorin: 500 mg/m2 on day 1 of every week for 6 weeks
5-Fluorouracil: 500 mg/m2 on day 1 of every week for 6 weeks
Duration of each cycle is 8 weeks and 3-4 cycles can be given.

BREAST CANCER
• FEC regimen:
5-Fluorouracil: 350 mg/m2 on day I every 21 days for 3 cycles
Epirubicin: 100 mg/m2 on day 1 every 21 days for 3 cycles
Cyclophosphamide: 350 mg/m2 on day 1 every 21 days for 3 cycles

• CMF regimen:
Cyclophosphamide: 100 mg/m2 per day orally on days 1-14 every 4 weeks for 6
cycles.
Methotrexate: 40 mg/m2 iv on days 1 and 8 every 4 weeks for 6 cycles.
5-Fluorouracil: 600 mg/m2 iv on days 1 and 8 every 4 weeks for 6 cycles.

ANAL CANCER
• 5-FU+Cisplatin regimen:
5-fluorouracil: 750 mg/m2 per day on days1-4 every 21 days for 2 cycles
Cisplatin:100 mg/m2 on day1 every 21 days for 2 cycles.
• Mitomycin+5-FU regimen:
Mitomycin: 10 mg/m2 on day1 every 28 days for 2 cycles
5-FU: 1000 mg/m2 per day on days1-4 every 28 days for 2 cycles

BLADDER CANCER
MVAC regimen:
Methotrexate: 30 mg/m2 on days 1,15,22 every 4 weeks for 6 cycles
Vinblastine: 3 mg/m2 on days 2,15,22 every 4 weeks for 6 cycles
Doxorubicin: 30 mg/m2 on day 2 every 4 weeks for 6 cycles
Cisplatin: 70 mg/m2 on day 2 every 4 weeks for 6 cycles.

HODGKIN’S LYMPHOMA
• BEAM regimen:
B-Carmustine(BCNU) 300 mg/m2 on day -7
E-Etoposide 150 mg/m2 every 12 hours on days -7 to -4
A-Cytarabine(Ara-C) 200 mg/m2 every 12 hours on days -7 to -4
M-Melphalan 140 mg/m2 on day -3
Hematopoeitic stem cell transplantation occurring on day 0.

• ABVD regimen:
A-Doxorubucin(Adriamycin) 25 mg/m2 on days 1 and 15 every 28 days
B-Bleomycin 10 units/m2 on days 1 and 15 every 28 days
V-Vinblastine 6 mg/m2 on days 1 and 15 every 28 days
D-Dacarbazine 150 mg/m2 on days 1-5 every 28 days

• Stanford V regimen:
Doxorubicin: 25 mg/m2 on days 1 and 15 every 28 days for 3 cycles
Vinblastine: 6 mg/m2 on days 1 and 15 every 28 days for 3 cycles
Mechorethamine: 6 mg/m2 on day 1 every 28 days for 3 cycles
Vincristine: 1.4 mg/m2 on days 8 and 22 every 28 days for 3 cycles

NON-HODGKIN LYMPHOMA
• EPOCH regimen:
Etoposide: 50mg/m2 IV on days 1-4
Prednisolone: 60 mg2/m PO on days 1-5
Oncovin: 0.4 mg/m2 IV on days 1-4
Cyclophosphamide: 750 mg/m2 IV on day 5
Hydroxydaunorubicin: 10 mg/m2 IV on days 1-4
The cycle can be repeated every 21 days.

• CHOEP regimen:
Cyclophosphamide: 750mg/m2 on day 1
Hydroxydaunorubicin: 50mg/m2 on day 1
Oncovin: 2 mg on day 1
Etoposide: 100 mg/m2 on days 1-3
Prednisolone: 100 mg/day on days 1-5
The cycle can be repeated every 21 days.

SIDE EFFECTS
Common to all cytotoxic drugs:
• Bone marrow supresseion
• Oral mucosa ulceration and Intestinal denuduation
• Alopecia
• Hyperuricemia
• Nausea and vomiting (DOC: 5-HT3 antagonists eg: Ondansetron, Granisetron,
Tropisetron, Palanosetron). However, for delayed vomiting due to cisplatin DOC
are Neurokinin(NK1) receptor antagonists (Aprepitant, Netupitant, Rolapitant).

Side-effects specific to some drugs:
• Cyclophosphamide and Ifosfamide may cause Hemorrhagic cystitis.
• Ifosfamide is the most neurotoxic cytotoxic drug. It may cause altered sensorium,
coma, cerebellar ataxia, seizures.
• Busulfan may also cause seizures.
• Busulfan and BCNU may cause vascular endothelial damage and may precipitate
veno-occlusive disease of liver. Defibrotide is FDA approved for the treatment of
veno-occlusive disease of liver.
• Alkylating agents may cause secondary cancers, particularly leukemias.

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