Cancer
• Cancer accounted for 7.1 million deaths world-wide
(12.5%).
• Ranks as 3 of the top 10 leading causes of death world
wide.
• 11 million are diagnosed with cancer each year and by
2020 the World health organisation expects this rise to 16
million.
• Second cause of death in the West (after cardiovascular
diseases).
Sources: WHO and Cancer Research UK
Pathogenesis of cancer
• DNA mutations
– Inborn mutations of cancer susceptibility genes
– Acquired mutations
• Other epigenetic factors
– Chemical carcinogens
– Virus-induced cancer
– X-rays
– Other risk factors (tobacco, alcohol, Asbestos, diet)
Cancer
• Genetic mutations within a single affected
cell leads to monoclonal development. Genes
affected can be those controlling cell cycle,
DNA repair and/or differentiation, This leads
to uncontrolled proliferation and tumour
formation.
Cancer Types
categorized based on the functions/locations of the cells from
which they originate:
– Carcinoma: a tumor derived from epithelial cells, those cells
that line the surface of our skin and organs (80-90% of all
cancer cases reported)
– Sarcoma: a tumor derived from muscle, bone, cartilage, fat
or connective tissues.
– Leukemia: a cancer derived from white blood cells or their
precursors.
– Lymphoma: a cancer of bone marrow derived cells that
affects the lymphatic system.
– Myelomas: a cancer involving the white blood cells
responsible for the production of antibodies (B
lymphocytes).
Causes of cancer
• 30% of cancer is due to smoking.
• 30% of cancer cases is diet related.
• 15% of cases are viral related infections:
– Papilloma virus… sexually transmitted… cause cervical
cancer.
– Hepatitis-B is the cause of 80% of liver cancer.
• Some are bacteria related:
– H.pylori…. Leads to stomach cancer.
The Classification of Anticancer
Drugs

According to chemical structure and resource of the drug:
– Alkylating Agents
– Anti-metabolite
– Antibiotics
– Plant Extracts
– Hormones
Problems with chemotherapy
• Treatments are non-specific, attack healthy cells as
well as normal cells since cancer cells are derived from
normal cells.
• Cancers can develop resistance: for example with
platinum-drugs, cancer cells became resistant by many
ways:
–
–
–
–
Decreased drug uptake/increased efflux
Enhanced tolerance of DNA adducts
Enhanced repair of DNA adducts
Increased drug deactivation by intracellular glutathione
Ideal cytotoxic drugs should:
• Selectively target cancer cells without causing damage to
normal cells.
• Reduce size of tumors + minimize risks of metastases.
 unfortunately, most of the available agents are not
selective, they also affect rapidly-proliferating
normal tissues (bone marrow, gastro intestinal
epithelium, hair cells, …), causing serious side-effects
(bone marrow suppression, nausea, vomiting, …).
alkylating agents
•
•
•
•
•
•
Nitrogen mustard
Nitrosourea
Busulfan
Cisplatin and Cisplatin Analogues
Dacarbazine and Procarbazine
Mitomycin C
Chemical Warfare – circa 1914
• Two most common agents:
• Chlorine gas
• Mustard gas
Cl
S
Cl
R
Cl
Sulfur Mustard
(chemical weapon) not
used clinically
N
Cl
Nitrogen Analog
Alkylating Agents
Mechanism of Action
• Nitrogen mustards inhibit cell reproduction by
binding irreversibly with the nucleic acids (DNA).
The specific type of chemical bonding involved is
alkylation. After alkylation, DNA is unable to
replicate and therefore can no longer synthesize
proteins and other essential cell metabolites.
Consequently, cell reproduction is inhibited and
the cell eventually dies from the inability to
maintain its metabolic functions.
Alkylating Agents
• Alkylating agents are reactive compounds that act on DNA, RNA
or enzymes.
• Cells are killed by the alkylation of DNA
– Formation of a covalent bond between drug and DNA (usually
N7 on G) to form crosslinks
– Methylation at N7
• Procarbazine, streptozocin, dacarbazine, temozolomide
• Drug resistance is common
nitrogen mustard
• nitrogen mustard
• amino acid, nucleic base or hormone uptake by carrier protien
Melphalan
Cl
Uracil Mustard
CH3
N
H 2N
H
COOH
N
HN
Cl
O
L-phenylalanine
(amino acid)
Estramustine
O
N
H
CH3
H
CH3
O
Cl
Uracil
(nucleic base)
OH
N
H
H
O
Cl
Estradiol
(sex hormone)
H
Nitrogen Mustard
+
chloroethylamino structure (NCH2CH2-Cl)
Cl
nucleophile
H 3C
Cl
N
electrophile
-s y s te m
s tru c t u re
Cl
Mechlorethamine (or Chlormethine)
N
Electrophilic carbon
Cl
MOA: Nitrogen Mustards
Generation of highly reactive “aziridinium ions” that act as alkylating
agents to cross-link DNA producing defective DNA and abnormal
cellular function and eventually cell death
Cl
H 3C
Cl
N
-
O
H 3C
NH2
HN
N
N
N
N
N
Cl
Cl
N
N
H 2N
O
NH2
HN
N
N
H 3C
O
NH
O
N
N
N
N
Cl
H 2N
NH
HN
O
H 3C
O
N
N
N
NH2
N
N
NH
O
N
N
N
2
N
N
N
NH
HN
HN
NH
N
O
NH2
N
H 3C
2
N
N
Nitrogen Mustards
Cl
H3 C N
HCl
Cl
Mechlorethamine HCl - Mustargen®
Extravasation a problem – 0.16
M sodium thiosulfate and ice
packs, {antidote for
extravasation} highly reactive
aziridinium ion
N,N-bis(2-chloroethyl)methylamine Injection only, monitor renal,
hepatic and bone marrow
MOST reactive of the
mustards
Nitrogen Mustards
Theoretical rationales used to improve nitrogen mustards
-Substituting an aromatic ring for methyl group can be predicted to
increase chemical stability and thereby decrease the rate of alkylation
because of electron-withdrawing effect.
This also, will lead to good oral bioavailability, tissue distribution,
before alkylation is widespread.
E.g. Chlorambucil, and melphalan.
Cl
N
Cl
(CH 2) 3-COOH
Chlorambucil
4-(p-bis(2-Chloroethylamino)phenyl)butyric acid.
Synthesis
CH3
HO
Nitration
O2 N
(CH2)3-COOH
CH3
(CH2)3-COOH
4-Phenylbutyric acid
CH3
CH3
(CH2) 3-COO-
O2 N
O
(CH2)3-COO-
H2N
CH3
2
CH3
Ethylene oxide
(oxirane)
Cl
HO
CH3
N
CH3
POCl 3
N
(CH2)3-COO-
(CH2)3-COO-
Phosphoryl chloride
CH3
CH3
Cl
HO
Cl
Hydrolysis
N
Chlorambucil
Cl
(CH 2) 3-COOH
Nitrogen Mustards
Cl
N
H2N
Cl
HO2C
Melphalan - Alkeran®
Oral or IV, severe bone marrow
suppression resulting in infection and
bleeding
Dosage reduction may be necessary in
renal failure as measured by BUN
Known to cause chromosome
abnormalities
Cl
R
N
NuH
Fast
Cl
Cl
N
R
Cl
Moderate
R
N
Nu
2- order kinetics
Nu
1. order kinetics
(1. step rat lim)
Nu
1. order kinetics
(1. step rat lim)
+ HCl
R=Alkyl
Cl
N
NuH
Slow
Cl
Cl
N
Ph
Cl
Moderate
Ph
N
+ HCl
Lone pair delocalized
Less nucleophilic
Cl
S
NuH
Slow
Cl
Cl
S
Cl
Moderate
less stable than N-aanalog
S
+ HCl
Nitrogen Mustards
To increase selectivity, nitrogen
mustards was bonded with natural
carrier e.g. estramustine which is
active against prostate cancer,
another examples is the bonding
with antimetabolites e.g. uracil
mustard.
Estramustine phosphate
Estracyt®
Pro-drug
O
O P O
O
OH
Na
Na
Cl
O
N
1) Oral absorb
2) Fast metabol.
Cl
Estradiol
Carry to cells with
estrogenic receptors
O
N
O
O
Water solubility
Cl
Cl
Main comp. plasma
Estrogenic (Anti-androgenic) effect protate
cancer
Cleaved to active alkylating agent?
Ideal cytotoxic drugs should:
• Selectively target cancer cells without causing damage to
normal cells.
• Reduce size of tumors + minimize risks of metastases.
 unfortunately, most of the available agents are not
selective, they also affect rapidly-proliferating
normal tissues (bone marrow, gastro intestinal
epithelium, hair cells, …), causing serious side-effects
(bone marrow suppression, nausea, vomiting, …).