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Basic principles of chemotherapy BY JITENDRA BHANGALE
1.
7/19/2012
By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage Learning 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 Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad2 © 2010 Smt N. M. Padalia 1
2.
7/19/2012 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, Delmar, Cengage Learning Pharmacy College, Ahmedabad3 © 2010 Smt N. M. Padalia 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad4 © 2010 Smt N. M. Padalia 2
3.
7/19/2012 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad5 © 2010 Smt N. M. Padalia 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad6 © 2010 Smt N. M. Padalia 3
4.
7/19/2012 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 synthesis By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad7 © 2010 Smt N. M. Padalia 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad8 © 2010 Smt N. M. Padalia 4
5.
7/19/2012 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad9 © 2010 Smt N. M. Padalia 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. 10 © 2010 Delmar, Cengage Learning 5
6.
7/19/2012 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. 11 © 2010 Delmar, Cengage Learning In Staphylococcus aureus, the five glycine residues are attached to the peptide chain at this stage 12 © 2010 Delmar, Cengage Learning 6
7.
7/19/2012 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. 13 © 2010 Delmar, Cengage Learning The lipid then loses one phosphate group and thus becomes available for another cycle. 14 © 2010 Delmar, Cengage Learning 7
8.
7/19/2012 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. By Jitendra Bhangale 15 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 position By Jitendra Bhangale 16 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 8
9.
7/19/2012 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 cells By Jitendra Bhangale 17 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia The incoming tRNA binds to the A site by complementary base pairing. Abnormal codon:anticodon leads to misreading of the message. e.g. Aminoglycosides By Jitendra Bhangale 18 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 9
10.
7/19/2012 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 19 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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. By Jitendra Bhangale 20 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 10
11.
7/19/2012 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. By Jitendra Bhangale 21 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 22 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 11
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