Transcript Cytotoxic drugs II.ppt

II- Antimetabolites
II- ANTIMETABOLITES
(Structural Analogues)
Antimetabolites are structurally
related to normal cellular
components
 MOA: block one or more of the
metabolic pathways involved in DNA
synthesis
 Most antimetabolites interfere with
nucleic acid synthesis
(nucleotide synthesis)

II- ANTIMETABOLITES
They inhibit the
synthesis purine or
pyrimidine nucleotide or
by competing with them
in DNA or RNA
synthesis
 Their maximal cytotoxic
effects are S-phase and
are therefore cell-cycle
specific drugs (CCS)

Examples of Antimetabolites
Folic acid Antagonists:
Methotrexate (MTX)
Purines antagonists:
Mercaptopurine (6-MP)
Pyrimidines antagonists:
Fluorouracil (5-FU)
Folic Acid
Folic acid is needed for
the synthesis of the thymidine,
required for DNA synthesis
 Also, folate is essential for the
synthesis of purine nucleotides
which in turn are essential for
DNA synthesis and cell division
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DFR

Inhibition of dihydrofolate reductase (DFR)
A. Folic Acid Antagonists
Methotrexate (MTX)
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MTX is structurally related to folic acid and
acts as an antagonist of that vitamin by
inhibiting dihydrofolate reductase
This enzyme converts folic acid to its active,
coenzyme form (FH4); tetrahydrofolic acid
 Methotrexate has a higher affinity than
Folate for dihydrofolate reductase and thus
inhibits the enzyme = depleting intracellular
FH4
Lack of this cofactor (FH4) interrupts
the synthesis of thymidine, purine
nucleotides
 Thereby interfering with the
formation of DNA, RNA, and protein
leading to cell death
 MTX is cytotoxic during the S-phase
of the cell cycle.
 MTX has a greater toxic effect on
rapidly dividing cells
(GIT, oral mucosa, BM)

Therapeutic Uses
Methotrexate, is effective against acute
leukemia, choriocarcinoma, non Hodgkin’s
lymphoma in children, breast cancer and
head & neck carcinoma
 To induce abortion with misoprostol
 It is effective against certain
inflammatory diseases, such as:
 Rheumatoid arthritis
 Severe psoriasis

Adverse Effects
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Depression of the bone marrow
Damage to the epithelium of the GIT;
stomatitis, nausea, vomiting and diarrhea
Erythema, rash, urticaria, alopecia
High doses of MTX may cause renal
damage (crystalluria) so it is important to
keep the urine alkaline + hydration
Intrathecal administration lead to
meningeal irritation, stiff neck, headache
Hepatic and pulmonary toxicity
Leucovorin rescue
Large doses of MTX must be followed by 'rescue'
with folinic acid (a form of FH4)
Rescue
Folinic
normal cells by Leucovorin =folinic acid
acid bypasses the blocked enzyme and
replenish the folate pool
Tumor resistance to MTX
Decreased drug transport into the
cell
 Altered dihydrofolate reductase
enzyme -- lower affinity for MTX
 Increase in dihydrofolate reductase
enzyme concentration in the cell

II- ANTIMETABOLITES
They inhibit the
synthesis purine or
pyrimidine nucleotide or
by competing with them
in DNA or RNA
synthesis
 Their maximal cytotoxic
effects are S-phase and
are therefore cell-cycle
specific drugs (CCS)

B. Purine Antagonists
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6-Mercaptopurine impairs the synthesis
of purine nucleotide
After oral administration, 6mercaptopurine undergoes first-pass
metabolism, inactivated by xanthine
oxidase in the liver
Clinical uses: For remission induction
and maintenance therapy of acute
lymphatic leukemia.
MOA of 6-mercaptopurine
6-MP is activated inside cell
6-MP by
Hypoxanthine Guanine Phospho-Ribosyl Transferase
(HGPRTase)
Thiol inosine monophosphate
Toxic nucleotide (TIMP)
TIMP

Incorporated into DNA
“Non functional”
E needed for
purine synthesis
Tumor cell death
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Adverse effects:
Principal toxicity is BM depression
 N & V, diarrhea
 Hepatotoxicity
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Drug interaction:
Allupurinol; is used to inhibit xanthine
oxidase, to prevent hyperuricemia
associated with tumor cell lysis, inhibits
the breakdown of 6-MP and increases 6-MP
effects, toxicity so dose of 6-MP must be
reduced by at least 25%
C. Pyrimidine antagonists
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Fluorouracil (5-FU)
It is converted to the corresponding
deoxynocleotide (5-FdUMP) which inhibits
thymidylate synthetase
Inhibition of thymidylate synthetase leads
to suppression of the formation of
thymidine nucleotides. This results in
inhibition of DNA synthesis through
“Thymidine-less death”
MOA of Fluorouracil
5FU  5-FdUMP
inhibits Thymidylate synthetase
 synthesis of thymidine nucleotide 
 DNA synthesis
Cytotoxic effects on
both RNA and DNA
Thymidine-less death
Therapeutic Uses
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Fluorouracil is used primarily in the
treatment of slowly growing solid
tumors such as colorectal cancer,
cancer of breast, ovary, pancreas
A cream incorporating fluorouracil is
used topically for treating skin cancers
Toxic Effects:
 It
may lead to nausea, vomiting,
anorexia, diarrhea and alopecia
 Severe ulceration of the oral
and gastrointestinal mucosa
 Bone marrow depression
Microtubule inhibitors
Microtubules Inhibitors
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Mitototic spindle
is formed during
cell division
Microtubules Inhibitors
Vinca alkaloids
Vinblastine
Vincristine
CCS
Podophyllotoxins
Etoposide
Taxanes
Paclitaxel
Vinblastine and Vincristine
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Belongs to Vinca alkaloids
Both drugs are cell cycle-specific
(CCS) because they block mitosis
in metaphase
Therapeutic uses
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Vinblastine is used in testicular carcinoma,
Hodgkin’s disease
 Vincristine is used in the treatment of
acute leukemia in children, Wilm’s tumor, and
Hodgkin’s and non-Hodgkin’s lymphomas
Adverse Effects:
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Common adverse effects for both drugs
include cellulitis or phlebitis if the drugs
extravasate during injection
Nausea, vomiting, diarrhea, and alopecia
Toxicity of Vinblastine &
Vincristine
VinBlastine
Vincristine
NOT
myelosuppressant
Myelo-supression
Peripheral neuropathy:
Depressed deep tendon
reflex, paresthesia,
foot drop
Taxanes
 Paclitaxel
(Taxol) shows good
activity against metastatic
breast cancer and advanced
ovarian cancer
 Side effects; neutropenia ‼,
peripheral neuropathy
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Filgrastim ( granulocyte colony
stimulating factor)
IV. Cytotoxic Antibiotics
 Substances
of microbial origin
that prevent mammalian cell
division
 Some
antibiotics that affect
DNA in both microbial and
mammalian cells can be used in
cancer chemotherapy
Cytotoxic Antibiotics
(Antitumor Antibiotics)
 Dactinomycin
(Actinomycin D)
 Doxorubicin (Adriamycin)
 Bleomycin

As a rule, they should not be given
together with radiotherapy, as the
cumulative toxicity is very high
Dactinomycin (Actinomycin D)
Dactinomycin was the first antibiotic used
in cancer chemotherapy
 It affects cells in all phases of the cellcycle i.e. CCNS
 Dactinomycin is given intravenously, it
remains unchanged and is concentrated in
the liver and excreted in bile
 It does not cross the BBB
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Mechanism of action of
Dactinomycin
D
It intercalates, in the
minor groove of DNA,
D
between adjacent guaninecytosine pairs thus
Minor Groove preventing transcription
(through an effect on
topoisomerase II
that essentially unwinds
the DNA helix for
replication)
Therapeutic Uses
It is mainly used for treating
paediatric cancers
 with other drugs in the treatment
of Wilm’s tumor, gestational
choriocarcinoma
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Adverse Effects:
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Extravasation during injection
produces severe irritation and
cellulitis
Adverse Effects (cont.)
Bone marrow depression is the
major dose-limiting toxicity
(leucopenia and thrombocytopenia)
 Nausea, vomiting, diarrhea, oral
ulcers alopecia and skin eruptions
may also be noted
 Dactinomycin sensitizes to
radiation; inflammation at sites of
prior radiation therapy may occur
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Doxorubicin (Adriamycin)
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Doxorubicin (Adriamycin) is the
most commonly used member of the
anthracycline antibiotics, given IV
Mechanism of Cytotoxic Action:
 Doxorubicin exerts its cytotoxic actions
through 3 mechanisms:
1. intercalates in the DNA, to stabilize
the DNA-topoisomerase II complex thus
halting replication
 binding
to cell membranes to
alter fluidity and ion transport
 generation of oxygen free
radicals (hydrogen peroxide) through
interaction with molecular oxygen
 This action may be responsible for
cardiac toxicity
(dysrhythmias and heart failure)
 The heart is devoid of superoxide
dismutase (SOD) which protects
tissues against oxygen free radicals
Clinical indications of Doxorubicin
 One of the most important and
widely used anti- cancer drug,
used in combination with other
agents in treatment of sarcomas
and cancer of breast, lung ,
ovary and thyroid gland
 It is useful also in acute
lymphoblastic leukemia, and
lymphomas
Adverse Effects:
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Extravasation causes tissue necrosis
The drug may lead to severe alopecia at
standard dosage ***
Stomatitis and GIT disturbances
Increased skin pigmentation
Doxorubicin causes bone marrow
depression which is of short duration,
with rapid recovery
The drug has dark red color and leads
to red color of the urine
Adverse Effects (cont.)
Doxorubicin cause cumulative, dosedependent cardiac toxicity, leading to
dysrhythmias cardiomyopathy and heart
failure due to generation of free
radicals and lipid peroxidation
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Dexrazoxane , an iron chelator ,
decrease the formation of superoxide
radicals is used to protect against the
cardiotoxicity of the drug
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Bleomycin: a metal-chelating
antibiotic
DNA- bleomycin-Fe2+ complex
intercalate between
base pair
B Fe
DNA- bleomycin-Fe3+
The liberated electrons
react with oxygen
B Fe
Generate free radicals
(superoxide, hydroxyl radicals)
DNA strands fragmentation
Clinical uses of Bleomycin
Bleomycin is most effective in the G2
phase of the cell cycle and mitosis, but
it is also active against non-dividing cells
(i.e. cells in the G0 phase)
CCNS
It is used to treat germline cancer
 Testicular carcinoma
 Hodgkin’s lymphoma
Adverse effects of
Bleomycin
Skin toxicity: Alopecia , blisters and
hyperkeratosis
Hypersensitivity reactions; fever, chills,…
It is not a myelosuppressant
V. Miscellaneous
Anticancer Agents
V- Miscellaneous Agents
L-Asparaginase
 Hydroxyurea
 Mitotane
 Retenoic acid derivatives
 Interferon
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L- Asparaginase
Asparagine is amino acid required for
protein synthesis
 Most normal cells can synthesize
asparagine
 Neoplastic cells require an external
source of asparagine (from the plasma)
because of their limited capacity to make
sufficient asparagine to support growth
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L-Asparaginase
L-asparaginase
Asparagine
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aspartic acid
+Ammonia
 L-Asparginase is derived from bacteria
L-asparaginase hydrolyzes serum asparagine and
thus deprives the tumor cells of this nutrient
required for protein synthesis
Most normal cells can synthesize asparagine and
thus are less susceptible to the action of
asparaginase
Theraputic uses:
 L-asparginase
is used to treat
childhood acute lymphocytic
leukemia in combination with
vincristine and prednisone
Adverse effects:
Hypersensitivity reactions, liver
affection and pancreatitis
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Hydroxyurea
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Hydroxyurea is an analog of urea.
MOA: blocks the incorporation of the
thymidine nucleotide into the DNA
strand.
used in chronic myeloid leukemia
administered orally.
Miscellaneous Agents
Mitotane
 Reduces excessive steroid
secretion
 used for Adrenal carcinoma
 Retenoic acid derivatives
Remissions -- acute leukemia
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Drug combinations
The administration of combinations of
drugs in the treatment of cancer produces
better results than a single drug
 A combination of drugs with different
toxic effects and affecting different
biochemical pathways has higher antitumor activity without additive toxicity
 Therapy is given intermittently to allow
recovery of normal tissue i.e. bone marrow
and immune system that has been
affected by the drugs
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Examples of drug
combinations
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Acute lymphocytic leukemia:
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Advanced breast cancer :
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Non-Hodgkin's lymphomas:
vincristine, methotrexate and 6mercaptopurine
Doxorubicin, cyclophosphamide with or
without flurouracil
Cyclophosphamide, doxorubicin,
vincristine