Folic acid antagonist

Methotrexate Leucovorin Pemetrexed

- Prevent lethal effects of methotrexate on normal cells - It works by inhibiting three enzymes used in purine and pyrimidine
SAR: by: synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and
1- Alkylation of amino groups decreased activity. - overcoming the blockade of tetrahydrofolic acid glycinamide ribonucleotide formyl transferase (GARFT).
2- Partial reduction, removal or relocation of heterocyclic nitrogen production.
decrease activity. - Inhibit active transport of methotrexate into cells and - By inhibiting the formation of precursor purine and pyrimidine nucleotides,
3- Glutamine are donner of nitrogen atoms of purine and guanine. stimulate its efflux. pemetrexed prevents the formation of DNA and RNA, which are required for
the growth and survival of both normal cells and cancer cells.
Assay: non aqueous titration, UV - Thymine deficiency (lethal effects).
- should take folic acid and vitamin B12 supplement even if levels are normal
when they are on pemetrexed therapy (In clinical trials for mesothelioma, folic
acid and B12 supplementation reduced the frequency of adverse effects.
- Folic acid cycle is the source of one carbon moiety needed to
convert uracil to thymine. N-formyltetrahydrofolic acid (Leucovorin, citrovorum)
- Methotrexate inhibits dihydrofolate reductase enzyme which
converts dihydrofolic acid to tetrahydro folic acid Accordingly stops - Is formyl donner to 5-amino imidazole-4-carboxamide in
the folic acid cycle and depletes the cellular system from thymine biosynthesis of purine
which is needed for DNA biosynthesis. - Carries the formimino group for synthesis of
Metabolism: formiminoglycine a precursor of purine

1- Converted to 7-OHMTX in liver by aldhyde oxidase.

2- Converted to diaminomethyl peteroic acid (DAMPA) by bacterial
carboxypeptidase enzyme in GIT

Rational:
MTX enter the cells through memberane folate binding protein (MFBP).
- Some tumours lack or have reduced MFBP, therefore, the uptake of
MTX in these tumours is not achieved after normal doses.

- High dose MTX is required to increase the extracellular levels of

MTX. Under these condition, MTX is transported by passive
diffusion.
- In high dose MTX therapy, the uptake of MTX into tumour cells is
highly selective because the affinity of MFBP to MTX is higher (1
uM) than normal cells (90 uM).
- Also, high dose MTX therapy improves its penetration into tumour
sanctuary sites such as testis, CNS and blood brain barrier.
 Purine antagonists
Antimetabolite purine and pyrimidine
6- Mercaptopurine (6MP) 6-thioinosinate Azathioprine
Anti-metabolites as a purine (azathioprine,
mercaptopurine) or a pyrimidine, chemicals

that become the building-blocks of DNA.

They prevent these substances from

becoming incorporated into DNA during the S
phase (of the cell cycle), stopping normal
- immunosuppressive medication. 1- inhibitor of conversion of phosphoribosyl - 6-[(1-Methyl-4-nitro-1H-imidazol-5-yl) sulfanyl]- development and cell division. Anti-
- It is used to treat acute lymphocytic leukemia, pyrophosphate into phosphoribosylamine 7H-purine. metabolites also affect RNA synthesis.
Crohn's disease, and ulcerative colitis. It is a 2- inhibit conversion of inosinic to adenylic - Azathioprine, is an immune suppressive However, because thymidine is used in DNA
thiopurine. 3- inhibit oxidation of inosinic to xanthylic acid medication.
but not in RNA (where uracil is used instead),
4- act as substrate for methyl transferase - It is used in rheumatoid arthritis, Crohn's
- Must be Converted to ribonucleotide( 6- disease, ulcerative colitis, and in kidney inhibition of thymidine synthesis via
thioinosinate) by Hypothanthine-guanine transplants to prevent rejection. thymidylate synthase selectively inhibits DNA
phosphoribosyl transferase.. - It is Prodrug of 6-mercatopurine synthesis over RNA synthesis.

Pyrimidine antagonist ‫ مش هنا‬22‫ و‬17 ‫سليد رقم‬

5-Flourouracil Cytarabine(arac) Capecitabine

- 5-Fluoro-2,4-(1H,3H)pyrimidine-dione - Cytarabineis cytotoxic to a wide variety of

- 5-FU mimics Uracil biologically with stronger actively dividing mammalian cellsinterfering - Colorectal cancer, Breast cancer Gastric
binding to thymidylate synthase. cancer and Oesophageal cancer.
with pyrimidine synthesis
Why we use 5- fluoro? - use: acute myelocyticleukemia.
- Increased acidity of fluorine cause molecule to - Prodrug of 5-flurouracil.
bind stonglyto Enz. - Gemcitabine: analogue of cytarabine,
- Size of fluorine nearly size of H. gemcitabine triphosphate (active form)use:
- so 5-FU prevents the methylation of C5 by solid tumor, first-line treatment alone for
thymidylate synthase causing its inhibition.
pancreatic cancer.
-
Use: neoplasm of breast, G.I. tract, carcenoma of
pancreas, urinary bladder, colon.

Mechanism of action: Metabolism: Metabolism:

1- Incorporation of FUTP (false nucleotide) instead of
UTP into RNA, interferes with RNA synthesis and
function.
2- Inhibition of thymidylate synthase by (FdUMP)
leads to depletion of TMP and TTP.
3- 3- Incorporation of FdUTP into DNA may affect
DNA stability.
 Antibiotics
Actinomycines Anthracyclines Bleomycins

- Antimetabolites may also be antibiotics,

such as sulfanilamide drugs, which inhibit
dihydrofolate synthesis in bacteria by
competing with para-aminobenzoic acid
- Opening of a lactone ring or change the - Produced naturally from Streptomyces species - Bleomycins is inactivated by bleomycins (PABA). PABA is needed in enzymatic
stereochemistry of an amino acid abolishes hydrolase enz. reactions that produce folic acid, which
activity. - They have a planar anthraquinone nucleus. - increases pKa of amino group, poor binding to acts as a coenzyme in the synthesis of
- Replacement of 2-amino, 4,6-methyl group by - They chelate with Ca, ferrous. DNA, chelation, reduce OH radicals. Resistance purines and pyrimidines, the building-
other substituents,(reduce activity). - They exhibit biological effect Similar to
blocks of DNA. Mammals do not
- actinomycines,
- Change in substituents influence their binding , - Light sensitive, should be handled with care synthesize their own folic acid so they are
less active (reduce activity). unaffected by PABA inhibitors, which
selectively kill bacteria.
- Assay: Chromatography. - Sulfanilamide drugs are not like the
antibiotics used to treat infections.
- Phenoxazone 1,9-dicarboxylic acid (actinocin)
Instead, they work by changing the DNA
inside cancer cells to keep them from
- Two identical pentapeptide lactone
(isoactinomycins) Different lactones are called growing and multiplying.
anisoactinomycins D actinomycin)
Natural products
1-Antibiotics

- Antitumor antibiotics are a class of

antimetabolite drugs that are cell cycle
nonspecific. They act by binding with DNA
molecules and preventing RNA (ribonucleic
Mechanism of action - They form chelates with ferrous ions. acid) synthesis, a key step in the creation
- actinomycin D is have the ability to inhibit t - complex gives rise to OH and super oxide of proteins, which are necessary for cancer
ranscription. radicals which cause cleavage of cell survival.
- Actinomycin D does this by binding DNA at the phosphodiester bonds of DNA,
- Anthracyclines are anti-tumor antibiotics
transcription initiation complex and causes degradation of DNA strand and death
preventing elongation of RNA chain by RNA of the cell. that interfere with enzymes involved in
polymerase copying DNA during the cell cycle.

Plant product
 Paclitaxol (Taxol) Colchicine Etoposide Vinca Alkaloids (Vinblastin,
Vincristine and Vindesine)

- Is a semi synthetic derivative of

- They cause mitotic arrest by
podophyllotoxin.
promoting the dissolution of
microtubules in cells
- It induce strand breaks in DNA mediated by
interaction with topoisomerase II.

- It is mitotic inhibitor. - Meadow saffron or autumn Crocus

- Used for breast, lung and poisonous
esophagus cancers cancer.

- Pacific Yew Tree

Anti-cancer agent used in treatment of

 Ovarian
 Testicular
 Lung
 Breast

Mechanism of action: Mechanism of action:

- Stabilizes microtubules and prevents - Tubulin binder
disassembly and re-polymerization - Inhibits tubulin polymerization

Monoclonal antibodies Trastuzumab Mabthera

Monoclonal antibodies (mAb or moAb) are
antibodies that are made by identical immune - Selectively binds with high affinity to - monoclonal antibodies directed against CD20
cells that are all clones of a unique parent cell. antigen found on the surface of normal and
extracellular domain of human
Monoclonal antibodies can have monovalent malignant b lymphocyte
affinity, in that they bind to the same epitope epidermal growth factor receptor 2
(the part of an antigenthat is recognized by the protein - Use: ttt of follicular CD20 positive, B cell NHL.
by the antibody ) - Use: breast cancer
- ( non hodjekin lymphoma ) in combination with CVP,
reumatoid arthritis in combination with
Bispecific monoclonal antibodies can also be - Do not mix with other medication, use
methotrexate.
engineered, by increasing the therapeutic immediately.
targets of one single monoclonal antibody to
two epitopes. - Acetominophen and antihistamines should
be taken to decrease infusion reaction.