Anti-Cancer drugs

Presented to Dr. Waseem Ashraf

Presenter Laiqa Qayyum Rao
11-PHL-S-23
Alkylating Agents

 Contain chemical groups that can form cross bridge covalent bonds with
DNA, as well as other nucleophilic substances in the cell.
 Alkylating agents form a carbonium ion-a cation, which is highly reactive
and react instantaneously with an electron donor(nucleophile) such amine,
hydroxyl or sulfonyl group
 The major site of alkylation within DNA is the N7 position of guanine
 To a lesser degree N1 and N3 of adenine, N3 of cytosine , O6 of guanine,
as well as phosphate atoms and proteins associated with DNA
 Eg; cyclophosphamide
Antimetabolites

 These block or subvert one or more of the metabolic pathways involved in DNA
synthesis
a) Folate antagonists eg; methotrexate
 Folates are essential for the synthesis of purine nucleotides and thymidylate,
which in turn are essential for DNA synthesis and division
 Methotrexate inhibits dihydrofolate reductase
 Dihydrofolate reductase convert the folate substrate (polyglutamates) first to
dihydrofolate(FH2) then to FH4
Cont…

 FH4 functions as an essential cofactor carrying the methyl groups

necessary for transformation of 2-deoxyuridylate(DUMP) to the 2’-
deoxythymidylate/deoxythymidine monophosphate(DTMP)
required for the synthesis of purines and DNA
Cont…

b) Purine antagonists- e.g 6-mercaptopurine, inhibits several enzymes

for purine biosynthesis. Also forms metabolites like 6-
methylmercaptopurine ribotide (MMPR) which contribute to its
cytotoxic action. Fludarabine in its triphosphate form inhibits DNA
polymerase
c) Pyrimidine antagonist- eg 5-fluorouracil, also inhibit thymidylate
synthetase hence inhibiting thymidylate synthesis
-Cytarabine; inhibits DNA polymerase
Cytotoxic Antibiotics

 Is a widely used group of drugs that mainly produce their effects through direct
action on DNA
 As a rule, they should not b given together with radiotherapy, as the cumulative
burden of toxicity is very high
a) Doxorubicin
 DNA intercalation, forms complexes with DNA strands and prevents
Topoisomerase|| activity consequent in cell cycle disruption and cell death
 Topoisomerase|| (a DNA gyrase); relaxes DNA super coils by nicking to facilitate
DNA replication/during RNA transcription
b) Dactinomycin

 Intercalates in the minor groove of DNA between adjacent

guanosine-cytosine pairs, interfering with the movement of RNA
polymerase along the gene and thus preventing transcription
 It affects mRNA and protein synthesis
 Also has an effect on topoisomerase||
c) Bleomycin

 Are group of metal-chelating glycopeptide antibiotics that degrade

performed DNA,
 DNA-Bleomycin-Fe+2 complexes undergo oxidation. Released
electrons react with oxygen to form superoxide or hydroxyl radicals
which attack phosphodiester bonds causing chain fragmentation and
release of free bases
 Bleomycin is most effective in the G2 phase, but it is also active
against non-dividing cells
Plant derivatives

a) Vinca Alkaloids
 Are derived from the Madagascar periwinkle
 The principal members are vincristine, vinblastine and vindesine
 The drugs bind to tubulin and inhibit its polymerization into
microtubules, preventing spindle formation in dividing cells and
causing arrest at metaphase
 Their effects become manifest only during mitosis
b) Taxanes

 Derived from the bark of yew tree

 They bind on microtubules, stabilizing them(in effect ‘freezing’
them) in the polymerized state, achieving a similar effect to that of
the vinca alkaloids by arresting mitosis
Miscellaneous Agents
Enzymes: L- Asparaginase
 Crisantaspase; is a preparation of enzyme asparaginase
 Inhibits Asparaginase synthase enzyme. It breaks down asparagine
to aspartic acid and ammonia. Inhibits protein synthesis-cell death.
 active against tumour cells that have lost the capacity to synthesize
asparagine and therefore require an exogenous source, such as those
of ALL
 The drug has a fairly selective action