Alkylating agents and antimetabolites are two classes of chemotherapy drugs. Alkylating agents work by binding to DNA and RNA, causing crosslinking or breaks that prevent replication. The main types are nitrogen mustards, alkyl sulphonates, nitrosoureas, and thiazines. Antimetabolites mimic normal metabolites and inhibit DNA or RNA synthesis by becoming incorporated. Major types are folate antagonists like methotrexate, pyrimidine analogs like 5-fluorouracil, and purine analogs like mercaptopurine. Both classes cause bone marrow suppression and gastrointestinal toxicity, and resistance can develop through drug inactivation or changes to drug targets.

1. ALKYLATING AGENTS
AND ANTIMETABOLITES

2. OBJECTIVE
 TO UNDERSTAND THE TYPE AND ROLE OF
ALKYLATING AGENTS
 TO UNDERSTAND THE TYPE AND ROLE OF
ANTIMETABOLITES

3. Alkylating Agent
 alkylating agent, any highly reactive drug that binds
to certain chemical groups (phosphate, amino,
sulfhydryl, hydroxyl, and imidazole groups) commonly
found in nucleic acids and other macromolecules,
bringing about changes in the DNA and RNA of cells.
 Alkylating agents were the first anticancer drugs used
 The types of molecular changes induced by alkylating
agents include cross-linking between strands of DNA
and the loss of a basic component (purine) from or the
breaking of the nucleic acid.

5. Con’t
 The result is that the nucleic acid will not be
replicated. Either the altered DNA will be unable to
carry out the functions of the cell, resulting in cell
death (cytotoxicity), or the altered DNA will change
the cell characteristics, resulting in an altered cell
(mutagenic change).
 This change may result in the ability or tendency to
produce cancerous cells (carcinogenicity).
 Normal cells may also be affected and become
cancer cells.

6. cont
 These molecules may either
 bind twice to one strand of DNA (intrastrand crosslink) or
 may bind once to both strands (interstrand crosslink).
 If the cell tries to replicate crosslinked DNA during cell
division, or tries to repair it, the DNA strands can break.
This leads to a form of programmed cell death called
apoptosis.

8. classes
 The alkylating agents are the largest group of
anticancer agents.
 Five main sub-groups.
1. Nitrogen mustards
2. Alkyl sulphonates
3. Nitrosoureas
4. Ethyleneimine
5. Thiazines

9. Nitrogen mustards
 Mechlorethamine: first nitrogen mustard.
 Used for Hodgkin and non-Hodgkin lymphomas
 It is also used topically for treatment of cutaneous T-
cell lymphoma .
 Toxicity: Block reproductive functions, First trimester
of pregnancy and later stage of pregnancy it should
not be used.
 Methclorethamine ,Cyclophosphamide,
Melphalan,Chlorambucil and Ifosfamide.

10. Alkyl sulphonates
 Busulfan – Highly specific for myeloid elements
and granulocyte .it is not curative.
 Toxicity: hyperuricaemia is common; pulmonary
fibrosis and skin pigmentation are specific
adverse effects.
 Drug of choice for chronic myeloid leukaemia .
 Dose: 2-6 mg/ day, orally

11. Nitrosoureas
 It is lipid soluble alkylating agents with a wide range of
antitumor activity
. Nitrosoureas: interfere with enzymes needed for DNA
repair.
 They are able to cross the blood-brain barrier.
 used to treat:
1. brain tumors
2. non-Hodgkin’s lymphoma,
3. multiple myeloma, and
4. malignant melanoma.
 Major toxicities occur in the hematopoietic and
gastrointestinal systems.
 Carmustine, lumustine, and streptozocin are examples
of nitrosoureas.

12. Thiazines
 Have primary inhibitory action on RNA and
protein synthesis (others mainly affect DNA).
 Ideal for malignant melanoma; also used in
Hodgkin's disease.
 Nausea and vomiting are prominent side effects.

13.  Alkylating agents can cause:
 severe nausea and vomiting
 as well as decreases in the number of red blood
cells and white blood cells.
 The decrease in the number of white cells results
in susceptibility to infection.
 Alkylating agents have found use in the
treatment of lymphoma, leukemia, testicular
cancer, melanoma, brain cancer, and breast
cancer. They are most often used in combination
with other anticancer drugs.

14. Antimetabolite
 similar in structure to a metabolite, or enzymatic
substrate, so competes with or inhibits the
metabolite.
 Their maximal cytotoxic effects are in S-phase
specific.
 readily become incorporated into either DNA or RNA
 cause toxicity In cells that are rapidly dividing
o Skin disorder, hair loss, anemia, mucositis,
myelosuppression and thrombocytopenia are common.

15. Antimetabolite as chemotherapeutic
1. Folate antagonist
2. Pyrimidine antagonist
3. Purine antagonist
4. Thymidylate synthase inhibitors
5. Multitargeted antifolate
6. Glycinamide ribonucleotide formyltransferase
and aminoimadazole carboxamide
ribonucleotide formyl transferase

16. Folate antagonist
 Methotrexate
 DHFR - conversion of dihydrofolate to
tetrahydrofolate and ultimately to 10-formyl
tetrahydrofolate which
 provides the formyl group for glycinamide
ribonucleotide formyl- transferase (GARFT) and
aminoimidazole carboxamide ribo- nucleotide
formyl transferase (AICARFT).
 Thus, the inhibition of DHFR results in depletion of
intracellular pools of reduced folates and ultimately
in reduced synthesis of purines and pyrimidines.

17. Mechanism
HN
N N
N
O
H2N
N
H
O
N
H
CO2H
CO2H
Folic acid
DHFR
HN
N N
H
N
O
H2N
N
H
R
Dihydrofolate
DHFR
HN
N N
H
H
N
O
H2N
N
H
R
Tetrahydrofolate
PABA
Microorganisms
HN
N N
H
N
O
H2N
N
R
Thymine synth
predominant mechanism of action of methotrexate is uncertain, as
polyglutamated forms of the drug also inhibit TS and AICARFT

18. Resistance
 Nonproliferating cells are resistant to MTX,
 probably because of a relative lack of DHFR.
 Decreased levels of the MTX polyglutamate due to
its decreased formation or increased breakdown.
 Resistance in neoplastic cells can be due to:
 amplification (production of additional copies) of the
gene that codes for DHFR, resulting in increased
levels of this enzyme.
 The enzyme affinity for MTX may also be
diminished.
 Resistance can also occur from a reduced influx of
MTX,

19. Indications
 MTX, effective against:
 acute lymphocytic leukemia,
 choriocarcinoma,
 Burkitt's lymphoma in children,
 breast cancer, and
 head and neck carcinomas.

20. Toxicity
 Renal damage: is a complication of high-dose MTX by
precipitating in the tubules.
 Hepatic function: Long-term use of MTX may lead to
cirrhosis.
 Pulmonary toxicity: This is a rare complication.
 Neurologic toxicities: associated with intrathecal
administration and include subacute meningeal
irritation, stiff neck, headache, and fever.
 Long-lasting effects, disabilities, have been seen in
children.

21.  Another DHFR inhibitor that has shown activity in
humans is piritrexim. This is compound does not
rely on the RFC, but enters the cell by means of
passive diffusion. It has oral bioavailability of 75%
 Trimetrexate is more lipophilic than methotrexate
and is not dependent on the RFC for entry into
the cell.
 This leads to higher concentrations of trimetrexate within
the cell, although the drug does not undergo
polyglutamylation.

22. Pyrimidine analogs
 It is widely used in colon cancer
 They include:-
 Fluorouracil
 CAPECITABINE
 CYTARABINE
 GEMCITABINE

23. 5-fluorouracil (5-FU)
 replacing nucleosides in one or more normal cell
functions because of their similarity
 Main use is in leukaemias, lymphomas,
colorectal cancer and solid tumors
 They may fall into one of two main classes
 either being incorporated into DNA and RNA
synthesis or
 being responsible for inhibition of one of the
enzymes essential to cell metabolism.

24. 5- FU prodrug capecitabine
 cytidine analogue is administered as an oral
formulation
 passes unchanged through the intestinal mucosa.
 activated through a series of enzymatic steps in
the liver and in tumour cells
 conversion to 5-FU in a potentially tumour-selective manner
by the enzyme thymidine phosphorylase
 Dose-limiting toxicities (DLT) included nausea,
mucositis, diarrhoea and neutropenia.

25. MOA
HN
N
O
O
O
HO
OP
O
OH
HO
5-FU metabolite
Thymidylate
Synthetase
HS
NHN
N
HN
N
O
NH2
R
B
H
HN
N
O
O
O
HO
OP
O
OH
HO
H
F
Thymidylate
Synthetase
S
B
NHN
N
HN
NH
O
NH2
R
F
Enzyme inhibition
HN
N
H
O
O
F
in vivo
HN
N
O
O
F
O
HO
OP
O
OH
HO
Inhibitor
Thymidylate synthetase
locks the enzyme into an inhibited conformation resembling the transition state
formed in the process of conversion of dUMP to thymidine by TS.

26. Resistance and adverse effects
 Resistance is encountered when the cells have
lost their ability to convert 5-FU into its active form
(5-FdUMP) or when they have altered or
increased thymidylate synthase levels.
 Adverse effects: anorexia, oral toxicity. A
dermopathy (erythematous desquamation of the
palms and soles) called the hand-foot syndrome
seen after extended infusions.

27. purines analogs
 6-THIOPURINES
 6-Mercaptopurine
 6-Thioguanine
 FLUDARABINE
 CLADRIBINE

28. 6-Mercaptopurine
is the thiol analog of hypoxanthine
Primarly serves in the treatment of childhood
acute leukemia
Mode of action is:-
Inhibition of purine synthesis:
 Incorporation into nucleic acids:
Nucleotide formation

29. 6-Mercaptopurine
Resistance:
1. an inability to biotransform 6-MP to the
corresponding nucleotide because of decreased
levels of HGPRT
2. increased dephosphorylation
3. increased metabolism of the drug to thiouric acid
or other metabolites.
4. Increased thiopurine methyltransferase (TMPT)
activity
Adverse effects:
 Bone marrow depression- principal toxicity. Side
effects (anorexia, nausea, vomiting, and diarrhea)

30. REFERENCE
 LIPPINCOAT’S PHARMACOLOGY
 LANG’S PHARMACOLOGY
 JOURNAL ON ANTIMETABOLITES
 WIKIPEDIA
 Cancer Research Campaign Department of
Medical Oncology, Beatson Oncology Centre,

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