Transcript Cancer

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
Causes of cancer
Multifactorial origin. Several factors associated with development of
malignancy :
1. Radiation (sunlight and radio frequency)
2. Chemical carcinogens (polyaromatic hydrocarbons)
3. Mutagens and viruses (Human papilloma virus)
4. Others: tobacco, alcohol, diet, asbestos,…
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.
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.
Tumor
benign
Is a tumor that lacks
the ability to
metastasize
Example: Thyroid
adenomas
Pre-malignant
Malignant (cancer)
If left untreated may
develop into cancer
medical term used to
describe a severe and
progressively
worsening disease
Examples: Atrophic
gastritis and Barrett’s
esophagus
is capable of invading
into adjacent tissues
Terminology – Cancer types
• Leukaemias are cancers of the blood or bone marrow.
• Sarcomas are cancers of the connective or supportive
tissue (bone, cartilage, fat, muscle, blood vessels) and soft
tissue.
• Carcinomas are cancers that arises from epithelial cells.
These include breast, liver, lung, stomach etc.
• Cancer metastasis is the spread of cancer from the
primary location to a secondary location.
Terminology – Side effects
• Neutropenia (or neutropaenia is a hematological
disorder characterized by an abnormally low number of
neutrophil granulocytes (a type of white blood cell).
• Myelosuppression is a decrease in the production of
blood cells. (Red blood cells and platelets).
• Ototoxicity is damage of the ear, specifically the cochlea
or auditory nerve.
• Nephrotoxicity is kidney damage. Results in decreased
kidney functions.
Terminology – Side effects
• Hepatotoxicity is liver damage. Results in decreased
liver function.
• Neuropathy is usually short for peripheral
neuropathy, and means a damage to peripheral
nerve(s).
• Hypomagnesaemia is an abnormally low level of
magnesium in blood serum.
Treatment
 Course of treatment will depend on the type of cancer, progress
of the disease, available treatment options and patients choice:
• Surgery
• Radiation
• Chemotherapy (including combination therapy)
• Gene therapy
• Natural products/herbal
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
Cancer treatment
 By surgery.
 By radiation.
 By anticancer drugs (cytotoxic agents):

Cytotoxic drugs of plant origin

Cytotoxic drugs of microbial origin

Antimetabolites

Alkylating agents

Platinum-based compounds
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, …).
Cytotoxic drugs of plant origin
 Vinca alkaloids
 Vincristine
 Vinblastine
 Vindesine
 Vinorelbine
OH
N
C2H5
Vincristine
N
N
O
O
HO
C2H5
CH3O
N
R HO
 Podophyllum lignans
 Podophyllotoxin
 Etoposide
O
H3C
H CO 2CH3
OH
OCOCH3
CO 2CH3
O
O
O
O
OH
O
Etoposide
O
O
H3CO
O
OCH3
OH
O
 Yew tree taxanes
 Paclitaxel
 Docetaxel
Podophyllotoxin
H3CO
O
OCH3
OCH3
O
NH
H3C
H3C
O
O
O
CH3
CH3 OH
O
CH3
OH
Vinca alkaloids mainly used for Leukemia
and lymphoma
O
OH
O O
O
Paclitaxel
O
CH3
Paclitaxel levels in plant is only
0.004%
O
O
O
NH
O
H
H3C
H3C
O
10
O
CH3
HO
CH3 OH
O
NH
O
O
OH
O O
O
CH3 OH
O
CH3
OH
O
O
CH3
CH3
OH
H3C
H3C
O
CH3
10-deacetylbaccatin III
(biosynthetic precursor)
O
OH
O O
O
O
CH3
Paclitaxel*, Docetaxel
(currently semi-synthesised)
Paclitaxel mainly used for breast cancer and ovarian cancer
O
OH
COCH2R
OH
OCH3 O
OH
O
O
H3C
NH2
OH
Doxorubicin
Daunorubicin
R= -OH
R= -H
Anthracyclines mode of action
DNA intercalation
OH
O
OH
O
Doxorubicin
O
H
H3C O
O
H3C
H
Guanosine
N
N
NH
N
OH
NH
H
N
NH
O
N
OH O
O
O
H
N
H
N
N
Guanosine
Hydrogen
bonding
O
Methylene bridge
H2C
O
OH
DNA intercalation will prevent action of topoisomerase II
(essential enzyme needed to untwist DNA)
Antimetabolites
Incorporated instead of a normal metabolite essential for
normal cellular division
Inhibit enzymes involved in the synthesis of a normal
metabolite essential for normal cellular division
Normal cell division is impaired
Folic acid
(diet)
O
N
H
CO2H
HN
O
N
HN
H2N
CO2H
N
N
GUT
Dihydrofolate
reductase
Folate inhibitors
Dihydrofolate
reductase
Dihydrofolate
Tetrahydrofolate
Methylenetetrahydrofolate
Thymidylate
synthetase
dTMP
(Thymidine)
DNA synthesis
dUMP
(uridine)
Methotrexate is an antifolate agent
O
CO2H
CO2H
N
H
HN
O
H2N
Folic acid
N
HN
N
N
Amine function
NH2
N
N
H2N
H3C
N
O
Methotrexate
CO2H
N
H
CO2H
N
Methyl group
Binds more strongly than folic
acid to DHFR and to carrier
protein which transports
folates into cells.
N
Cells are starved of thymine. DNA production is impaired.
Related to methotrexate structure
O
NH2
N
N
H2N
H3C
N
N
CO2H
N
H
N
CO2H
Fluorouracil
O
O
F
HN
HN
O
F
HN
O
N
H
Fluorouracil
O
OH
O
P
CH
O
OH 2
O
N
OH
O
P
CH
O
OH 2
5-FdUMP OH
dUMP
O
N
O
OH
5-fluorodeoxyuridine monophosphate binds irreversibly to the active site of
thymidylate synthetase (C-F bond) instead of deoxyuridine monophosphate.
Stops the production of thymidine
Used in solid tumors
Cytarabine
NH2
NH2
N
N
O
HOCH2
O
HO
OH
cytarabine
NH2
N
O
N
O
O
O
O
O
HO P O P
P
CH2 O
O
HO
HO
OH OH OH
HO
THYMIDYLATE
THYMIDINE
KINASE
KINASE
OH
OH
cytarabine monophosphate
cytarabine triphosphate
HO
O
O
P
CH2
O
N
N
Mimic
NH2
N
O
O
O
O
HO P O P O
P
CH2
OH OH OH
O
N
O
OH
Deoxycytidine triphosphate
Alkylating agents
 Very reactive agents that alkylate cell constituents (DNA,
enzymes, …).
 Possess a highly electrophilic centre (δ+) to react with
nucleophilic groups (Nu -) such as OH, SH, NH.
 The binding will be irreversible.
 No selectivity ( kill normal + cancer cells).
Mustards as alkylating agents
 Discovered after the development of sulphur
mustard, a chemical agent used during World War
1.
 Drugs cause depletion of white blood cells as s/e
Mustards – mode of action
Clinically used mustards
Orally available
through
phenylalanine
transport system
Clinically used mustards
Cyclophosphamide is a prodrug
OO
ClCH2CH2
N
ClCH2CH2
OO
H
P
N
N
ClCH2CH2
N
H
Cyclophosphamide
P
CH2CH2Cl
Phosphoramide group
Ifosfamide
OXIDATION IN LIVER
TUMOUR
O O CH2CH2Cl
P N
CH2CH2Cl
NH
HO
4-hydroxycyclophosphamide.
O
O O CH2CH2Cl
P N
NH2 CH2CH2Cl
aldophosphamide
tautomer.
b
a
O
HO O CH2CH2Cl
+ P N
NH2 CH2CH2Cl
acrolein
HO
O
phosphoramide
CH2CH2Cl
+ HN
P
HO NH
CH2CH2Cl
2
normustine.
Other alkylating agents
 Do not necessarily contain nitrogen mustard, but it
should have the electrophilic species which will react
nucleic acids:
 Di-epoxide forming compounds:
SO2CH3 OH
OCH2
CH CH CH2O
OH
CH2
CH CH CH2
O
O
SO2CH3
Treosulfan (prodrug)
p.o or IV
For ovarian cancer
Diepoxybutane
The active electrophile
Other alkylating agents
Ethyleneimine
group
N
N
N
Tretamine
N
N
S
N
P
N
N
N
Thiotepa
Bladder cancer
Busulfan
bis-sulphonic acid esters
safe enough to be given by
mouth.
site-specific delivery of cytotoxic
Mustine alkylating agents
 Prostate tumour cells have abundant oestrogen
receptor sites, and complexation of an Estradiol carrier
with normustine enables accumulation of the complex
within the tumour. The phosphate group provides
water solubility, and the Carbamate linkage between
the Mustine and the Estradiol deactivates the nitrogen
lone pair through resonance stabilization, rendering
the alkylating agent inactive when in the complex.
Enzymatic hydrolysis in the tumour cell releases the
active drug at the site of action.
Phosphate group improves water solubility
the change of the amino group into the carbamate
Has reduced the nucleophilicity of it….difficult
To form the aziridinium ring (less active)….prodrug
Platinum-based drugs
Cisplatin
Carboplatin
Oxaliplatin
They are prodrugs in general
Because this will increase
the extracellular Cl- concentration
compared to the intracellular
NH 3
Cl
Pt
NH 3
O H
H
Mechanism of action of cisplatin
Induces cellular apoptosis by forming coordinate bonds to N7
atom of guanosine and adenosine bases. Results in unwinding of
the DNA helix and a bend towards the major groove of up to 30o.
 This prevents DNA transcription and
Replication.
O
O
O
Guanine
O
O
N
P O
NH
7
O
N
O
NH 3
NH 2
Guanine
N
P O
NH
7
O
N
C H2
O
N
C H2
N
O
NH 3
Pt
Pt
NH 3 O
O
NH 3
OH
O
N
NH
7
O
N
C H2
OH
O
P O
O
O
OH
NH 2
O
N
P O
NH 2
Guanine
N
7
O
N
NH 2
N
C H2
O
O
O P O
O P O
O
O
C H2
C H2
OH
N
Adenine
Intras tran d addu cts be twe e n de oxygu an os i n es Intras tran d addu cts be twe e n de oxygu an os i n es
accou n ts for 60-65% of all addu cts forme d
an d de oxyaden os in e accou n ts for 20-25% of al l
addu cts forme d
guanine-platinum-guanine
guanine-platinum-adenine
Interaction of the aquatic species with DNA: Formation of intrastrand
bi-adducts blocking replication and/or prevent DNA transcription
Carboplatin
• Delivers the same active aquatic species as cisplatin, but with the chloride
ligands replaced with carboxylate.
• preferred first line drug for ovarian cancer and small cell lung cancer) and is
used particularly with patients who have poor tolerance of cisplatin.
O
O
H3N
Pt
NH3
O
O
Oxaliplatin
• First approved in 1999 for the use cisplatin and
carboplatin resistant cancers
• One of three enantiomers, only the R,Rdiaminocyclohexane ligand is active.
• Used primarily to treat colon/colorectal cancer.
Responsible for the
lack in cross-resistance
Good leaving group
Platinums in clinical trial
ZD0473 (120-150 mg/m2)
Overcome glutathionemediated resistance
JM216 (Satraplatin™)
Orally active
4+
NH3
NH3
H2
N
Cl
Pt
H3N
N
H2
Pt
NH3
H3N
H2
N
Cl
Pt
N
H2
NH3
BBR3464 (0.9-1.1 mg/m2) Active in a range of cisplatin resistant cell lines