Basics of Chemotherapy

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PHAR1001 Pharmacology
Basics of Chemotherapy Anti-malarias, HIV
Treatment Antibiotics
Dr Dean Willis Department of Pharmacology Universi
ty College London Gower Street, London WC1
6BT dean.willis_at_ucl.ac.uk
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Aims
To understand the basic concept of underlying the
use of chemotherapy to treat diseases.
Understand the life cycle of the Malaria parasite
and possible intervention points.
To understand the mode of action of anti-malaria
drugs.
Understand the life cycle (replication) of the
HIV and possible therapeutic intervention points.
Understand the mode of action of anti-HIV drugs.
Understand the concept behind combination therapy
Pharmacology. Rang, Dale Ritter 4th Edition
Chapters. 41, 44 46
Integrated Pharmacology. Page, Curtis, Sutter,
Walker Hoffman 2nd Edition Chapters 8 11
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World health organization most wanted diseases
Malaria People with malaria 300 million Malaria
related deaths per year 2.7 million
HIV People with HIV/Aids 42 million New HIV per
year 5 million (0.8 million Children) Aids
related deaths per year 3.1 million (0.6 million
Children)
Tuberculosis 8 million people become infected
with TB per year TB related deaths per year 2
million
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History of Chemotherapy
If we picture an organism as infected by a
certain species of bacterium, it will . . . be
easy to effect a cure if substances have been
discovered which have a specific affinity for
these bacteria and acton these alone. . . while
they possess no affinity for the normal
constituents of the body. . . such substances
would then be . . . magic bullets
Paul Ehrlich 1854-1915 Nobel Laureate 1908
Gertrude Belle Elion George Hitching Continued
this work and together with James Black was
awarded 1988 Noble prize
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Theory of Chemotherapy. The Idea
For the case of Chemotherapy bacteria, fungi,
protozoa, helminths, viruses and cancer cell are
considered parasites.
Find Qualitative (preferable) or Quantitative
Biochemical difference between Host and Parasite
which when exploited by a selective drug results
in a cytotoxic effect to the parasite but not host
Theory
The result
Drug
TD50
Therapeutic Index (TI)

Is large
ED50
Host
Parasite
No effect
Cytotoxic
With the on-set of genomics/proteomics and
systems Biology the theory of Chemotherapy could
be expanded to systemic chronic pathologies
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Theory of Chemotherapy. The problems
Bacteria/Protozoa have many differences, Viruses
have fewer (hijacking some of the hosts
biochemistry) Cancer is essentially self (rely on
quantitative differences
Development of resistance (adaptation/ mutation)
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Theory of Chemotherapy. The Targets
Class I Biochemical reactions (energy production)
Gycolysis, Catabolism of polysaccharides and
lipids, pentose phosphate pathway, pyruvate
oxidation, citric acid cycle, fermentation and
respiration
Class II Biochemical reactions (Small molecule
synthesis)
Biosynthesis of DNA, RNA, proteins, Lipoproteins,
peptidoglycans protein degradation, Cytoskeleton
assembly, Glycogen synthesis,
Class III Biochemical reactions (Macromolecule
production, polymers)
Biosynthesis of amino acids, Lipids, Coenzymes
(tetrahydrofolate), Purines Pyrimidines, heme
catabolism/metabolism
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Malaria
60 of worlds population live in areas were
malaria is endemic
Plasmodium falciparum Most serve form no
exoerythrocyte stage Plasmodium vivax less serve
than P. falciparum does have exoerythrocyte
stage Plasmodium ovale Rare does have
exoerythrocyte stage Plasmodium malariae
Widespread but no exoerythrocyte phase
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Malaria. Factors influencing therapy
Life cycle
Malarial species, strains
Protect (prophylactic)
Drug metabolism
Cure established infection
Side effects
Prevent malarial transmission
Hosts immunity
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Malaria. Anti-malarial drugs. The Folate pathway
C50 (mmol/l) for FH2 reductase
Human
Protozoal
Bacterial
Trimethoprim
260
0.07
0.005
Pyrimethamine
0.7
0.0005
2.5
Methotrexate
0.001
0.1
inactive
Sulphonamides Sulphones. Rely on the fact that
malaria synthesis folate and host does not
Proguanil pyrimethamine. Rely on the different
sensitivity of malaria and host dihydrofolate
reductases to antagonists
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Malaria. Anti-malarial drugs. Haem catabolism
Chloroquine, quinine mefloquine target another
qualitative difference between malaria and host,
that of heme catabolism
Malaria (Erythrocytic Cycle)
Host
Haemoglobin
Haemoglobin
Amino acids
Free Haem
Free Haem
Haem polymerase
Haem oxygenase
Haemozin
iron
CO
Bilirubin
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HIV infection
HIV replication.
Retrovirus Positive-strand RNA 15 genes
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Nucleotide structure
Bases
Pyrimidine
Purine
Uracil
Adenine
Cytosine
Guanine
Thymine
BASE SUGAR NUCLEOSIDE
BASE SUGAR PHOSPHATE NUCLEOTIDE
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Nucleoside Reverse Transcriptase inhibitors
DdC 2, 3-Dideoxycytidine
AZT 3-azido-3 deoxythymidine
DdI 2, 3-Dideoxyinosine
3TC 3-thiabofuranosyl-bL-cytosine
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Nucleoside Reverse Transcriptase inhibitors
mechanisms of action in HIV
AZT
Infected Cell
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Non-nucleoside Reverse Transcriptase inhibitors
(NNRTIs)
Nevirapine
C1-TIBO
L697-661
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Non-nucleoside Reverse Transcriptase inhibitors
(NNRTIs) mechanisms of action in HIV
Side-view Reverse Transcriptase
Top-view Reverse Transcriptase
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HIV Protease (aspartly protease) inhibitors
Viral Protease required for the splicing of viral
proteins which are polycistronic
GAG
POL
ENV
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Tomorrow we will look at
Anti-bacterial agents
How chemotherapeutic agents are combined
How theories of evolution and clinical use
of chemotherapeutic agents impact on drug
resistance