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Basic principles of chemotherapy BY JITENDRA BHANGALE

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  • 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 BhangaleAsst. 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 BhangaleAsst. 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 BhangaleAsst. 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 BhangaleAsst. 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 reactionsexist in parasitic but not in human cells.Pathways may be identical but there may bedifferential sensitivity to drugs.Folate synthesis is an example of metabolicpathway found in bacteria but not in man. By Jitendra BhangaleAsst. 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 BhangaleAsst. 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 BhangaleAsst. 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 BhangaleAsst. 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 andadded to the growing end of the peptidoglycan, the acceptor, with therelease 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 15Asst. 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 subunitwhereas 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 16Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 8
  • 9. 7/19/2012A ribosomes (with 3 bindingsites for t RNA: the P, A, and Esites).A tRNA with the growingpeptide chain is in the P site,bound by codon:anticodonrecognition. The incoming tRNAcarries valine covalently linked.Competition with tRNA for the Asite selectively largely throughselective uptake by activetransport 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 21Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 22Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 11