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Basic Principles of Chemotherapy - Coggle Diagram
Basic Principles of Chemotherapy
Chemotherapy
the use of synthetic chemicals to destroy infective agents which is also applied to inhibit growth of malignant or cancerous cells within the body
Antibiotics
substances produced by some microorganisms to kill or inhibit the growth of other organisms
Agents should ideally be maximally parasitotropic and minimally organotropic
Parasitic Cells
prokaryotes (cells without nuclei, eg bacteria)
contain peptidoglycan in their cell walls (EXCEPT Mycoplasma)
cell membrane of bacteria different than host's (has specific transport mechanisms for various types of nutrients)
Internal Osmotic Pressure
around 5 atmosphere in Gram-negative organisms
around 20 atmosphere in Gram-positive organisms
cell wall + cell membrane = envelope
lack mitochondria
Outer Membrane (outside cell wall)
found in gram-negative bacteria
relevant to chemotherapy
may prevent penetration of antibacterial agents
eukaryotes (cells with nuclei, eg Protozoa - unicellular, Helmints - multicellular)
viruses
cancer cells (problem for selective toxicity due to similarity to host cells)
Biochemical Reactions Involved in the Formation of Cell Structures
Class 1
utilisation of glucose or some alternative carbon source for the generation of energy (ATP) and of simple carbon compounds
not promising targets
Class 2
utilisation of the energy and precursors to make all necessary small molecules: amino acids, nucleotides, phospholipids, amino sugars, carbohydrates, and growth factors
better targets than class 1 reactions
some pathways involved in class 2 reactions exist in parasitic cells but not in human cells (eg folate synthesis - found in bacteria but not humans)
Sulfonamides
compete with PABA (para amino benzoic acid) for the enzyme involved in folate synthesis
Dihydrofolate reductase inhibitors
trimethoprim in bacteria, pyrimethamine in plasmodium, methotrexate in humans
Co-trimaxozole : trimethoprim + sulphamethoxazole
blockage of folate pathways with a combination of 2 drugs (more successful than the use of either alone)
relative specificity for FH2 reductase
Primidine & purine analogs
may be used in cancer chemotherapy
pyrimidine analogue : 5-fluorouracil
purine analogues : mercaptopurine, thioguanine
Flucytosine : antifungal drug which is deaminated to 5-fluorouracil in fungi (but not in host cells)
Class 3
assembly of the small molecules into macromolecules: proteins, RNA, DNA, polysaccharides, and peptidoglycan
particularly good targets for selective toxicity (every cell has to make its own macromolecules that cannot be picked from the environment) - eg peptidoglycan synthesis
Peptidoglycan
multiple backbones of amino sugars - alternating N-acetylglucosamine and N-acetylmuramic acid residues (have short peptide side chains which are cross-linked to form a lattice-work)
cross-linking => strength that allows cell wall to resist the high internal osmotic pressure
Peptidoglycan synthesis inhibitors
Cycloserine
structural analogue of D-alanine
prevents the addition of two terminal alanines to the initial tripeptide side chain on N-acetylmuramic acid
Vancomycin
inhibits release of the building block unit from the carrier - preventing its addition to the growing end of the peptidoglycan
Bacitracin
interferes with the regulation of lipid carrier by blocking dephosphorylation
Penicillins
cephalosporins and other beta-lactams inhibit the final transpeptidation that establishes the cross-links
Protein Synthesis
ribosomes are different in eukaryotes (60S & 40S) and prokaryotes (50S & 30S subunits)
competition with tRNA for the A site (tetracyclines)
abnormal codon : anticodon recognition leads to misreading of message (aminoglycosides - streptomycin)
inhibition of transpeptidation (chloramphenicol)
premature termination of peptide chain (puromycin - resembles amino acid end of tRNA)
inhibition of translocation (erythromycin + spectinomycin , fusidic acid)
Nucleic Acid Synthesis Inhibition
quinolones inhibit DNA gyrase (aka topoisomerase II - unwinds supercoiled DNA helix)