Basic principles of chemotherapy BY JITENDRA BHANGALE

7/19/2012

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© 2010 Delmar, Cengage Learning1

By- Jitendra Bhangale

Assistant Professor & Head,

Department of Pharmacology,

Smt N. M. Padalia Pharmacy College,

Ahmedabad


Chemotherapy: The use of synthetic

chemicals to destroy infective agents. Also

applied to inhibit growth of malignant or

cancerous cells within the body.

Antibiotics: Substances prduced by some

microorganisms to kill or inhibit the growth of

other organisms.

By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad

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Prokaryotes: Cells without nuclei

e.g. bacteria

Eukaryotes: Cells with nuclei e. g. Protozoa

unicellular, Helmints multicellular

Viruses even though they are not cells at all

Cancer cells are also foreign or parasites

but are more similar to normal host cells

than any other categories.By Jitendra Bhangale

Asst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad


Class I: The utilization of glucose or some alternative

carbon source for the generation of energy and some

carbon compounds.

Class II: the utilization of the energy and precursors to

make all necessary small molecules : amino acids,

nucleotides, phospholipids, amino sugars,

carbohydrates and growth factors.

Class III: Assembly of the small molecules into

macromolecules: proteins, RNA, DNA, polysaccharides

and peptidoglycan.


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Class I reactions are not promising targets.

There is no difference between bacterial and

human cells.

Even if glucose pathways were to be

blocked, a large variety of other compound

could be used by bacteria as alternatives.



Class II reactions are better targets.

Some pathways involved in class II reactions

exist in parasitic but not in human cells.

Pathways may be identical but there may be

differential sensitivity to drugs.

Folate synthesis is an example of metabolic

pathway found in bacteria but not in man.


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Class III reactions are particularly good

targets for selective toxicity, because every cell

has to make its own molecules that cannot be

picked from the environment.

Examples:

Peptidoglyan synthesis

Protein synthesis

Nucleic acid synthesisBy Jitendra Bhangale



Peptidoglycan constitutes the cell wall of bacteria

For Gram-negative organisms the bag consists of a single

thickness, but for Gram-positive organisms, it is up to

40 layers thick.

Each layer consists of multiple backbones of amino

sugars-alternating N-acetylglucosamine and

N-acetylmuramic acid residues

The latter having short peptide side-chains that are cross-

linked to form a latticework.


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The cross-linking is responsible for the

strength that allows the cell wall to resist

the high internal osmotic pressure.

The peptidoglycan is one gigantic molecule

with a molecular weight of many millions,

constituting up to 10-15% of the dry

weight of the cell.



First, N-acetylmuramic acid, which has attached to it both UDP

and a pentapeptide, is transferred to the C55 lipid carrier in

the membrane, with the release of UMP.

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This is followed by a reaction with UDP-N-acetylglucosamine,

resulting in the formation of a disaccharide carrying the

pentapeptide and attached to the carrier.


In Staphylococcus aureus, the five glycine residues are attached

to the peptide chain at this stage

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The 'building block' is now transported to the outside of the cell and

added to the growing end of the peptidoglycan, the 'acceptor', with the

release of the C55 lipid, which still has two phosphates attached.


The lipid then loses one phosphate group and thus becomes

available for another cycle.

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Cycloserine is a structural analogue of D-alanine and prevents

the addition of the two terminal alanines to the initial

tripeptide side-chain on N-acetylmuramic acid.

Vancomycin inhibits the release of the building block unit from

the carrier, thus preventing its addition to the growing end

of the peptidoglycan.

Bacitracin interferes with the regeneration of the lipid carrier by

blocking its dephosphorylation.

Penicillins, cephalosporins and other β-lactams inhibit the

final transpeptidation.



Protein synthesis takes place in the ribosomes.

The bacterial ribosome consists of a 50S subunit and a 30S subunit

whereas in the mammalian ribosome the subunits are 60S and 40S.

The other elements involved in peptide synthesis are messenger

RNA (mRNA), and transfer RNA (tRNA),

The ribosome has three binding sites for tRNA, the A, P and E sites.

mRNA, which is transcribed from DNA, becomes attached to the

30S subunit of the ribosome.

The 50S subunit then binds to the 30S subunit to form a 70S*

subunit, which moves along the mRNA so that successive

codons** of the messenger pass along the ribosome from the A

position to the P positionBy Jitendra Bhangale


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A ribosomes (with 3 binding

sites for t RNA: the P, A, and E

sites).

A tRNA with the growing

peptide chain is in the P site,

bound by codon:anticodon

recognition. The incoming tRNA

carries valine covalently linked.

Competition with tRNA for the A

site selectively largely through

selective uptake by active

transport into prokaryotic cellsBy Jitendra Bhangale



The incoming tRNA binds to the

A site by complementary

base pairing.

Abnormal codon:anticodon

leads to misreading of the

message.

e.g. Aminoglycosides


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Transpeptidation occurs i.e. the

peptide chain on the

tRNA in the P site is

transferred to the tRNA

on the A site.

The tRNA in the P site has been

discharged i.e. has lost its

peptides.

Premature termination of

peptide chain which

resembles the amino acid

end of tRNA.By Jitendra Bhangale



The tRNA from which the

peptide chain has been

removed is ejected.

A new tRNA, with amino acid

attached and with the

relevent anticodon, now

moves into the A site, and

the whole process is

repeated.


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By inhibiting the synthesis of the nucleotides

By altering the base-pairing properties of the

template

By inhibiting either DNA or RNA polymerase

By inhibiting DNA gyrase

By direct effects on DNA itself.




Basic principles of chemotherapy BY JITENDRA BHANGALE

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