ALKYLATING AGENTS

AND ANTIMETABOLITES

OBJECTIVE

TO UNDERSTAND THE TYPE AND ROLE OF

ALKYLATING AGENTS

TO UNDERSTAND THE TYPE AND ROLE OF

ANTIMETABOLITES

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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

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.

Mechanism

HN

N N

N

O

H2N

NH

O

NH

CO2H

CO2H

Folic acid

DHFR

HN

N NH

N

O

H2N

NH

R

Dihydrofolate

DHFR

HN

N NH

HN

O

H2N

NH

R

Tetrahydrofolate

PABA

Microorganisms

HN

N NH

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

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,

Indications

MTX, effective against:

acute lymphocytic leukemia,

choriocarcinoma,

Burkitt's lymphoma in children,

breast cancer, and

head and neck carcinomas.

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.

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.

Pyrimidine analogs

It is widely used in colon cancer

They include:-

Fluorouracil

CAPECITABINE

CYTARABINE

GEMCITABINE

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.

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.

MOA

HN

N

O

O

O

HO

OP

O

OH

HO

5-FU metabolite

ThymidylateSynthetase

HS

NHN

N

HN

N

O

NH2

R

BH

HN

N

O

O

O

HO

OP

O

OH

HO

H

F

ThymidylateSynthetase

SB

NHN

N

HN

NH

O

NH2

R

F

Enzyme inhibition

HN

NH

O

O

Fin vivo

HN

N

O

O

F

O

HO

OP

O

OH

HO

InhibitorThymidylate synthetase

locks the enzyme into an inhibited conformation resembling the transition state

formed in the process of conversion of dUMP to thymidine by TS.

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.

purines analogs 6-THIOPURINES

6-Mercaptopurine

6-Thioguanine

FLUDARABINE

CLADRIBINE

6-Mercaptopurineis 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

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) hepatotoxicity in one-third of adult patients.

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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