Principles of Chemotherapy

Gets to tumour via bloodstream
1. Reaches primary tumour and metastases
Kills cells by apoptosis
1. Has some toxicity to heathly cells
  1. Due to therapeutic window - gap between efficacy and toxicity
Combinations of chemotherapeutic drugs given in cycles
1. Treatment 1 is strong to reduce tumour size before surgery, irradiation and multiple course chemotherapy
  1. Treatment 2 is used to eliminate micrometastatic disease
Immunotherapy - Can be used to guide imaging of tumour
Drug examples
1. Pentostatin - inhibits adenosine deaminase
2. 6-Mercaptopurine and 6-Tioguanine - inhibit purine synthesis and nucleotide interconversions
3. Methotrexate - inhibits purine and DTMP synthesis
4. Cytarabine - inhibits DNA polymerase and RNA function
5. Crisantaspase - deaminates asparagine and inhibits protein synthesis
6. 5-Fluorouracil - inhibits DTMP synthesis
7. Bleomycins - damage DNA and prevent repair
8. Alkylating agents, Mytomycin and Cisplatin - cross-link DNA
9. Campothecins, Doxorubicin, Etoposide and Amsacrine - inhibit RNA synthesis and topoisomerase II
10. Dactinomycin - intercalates in DNA, inhibits topoisomerase II and RNA synthesis
11. Vinca Alkaloids and Taxanes - inhibit function of microtubules
Major Classes of Cytotoxics
1. DNA binding drugs
  1. Cause direct DNA damage and block DNA replication
  2. e.g. alkylating agents and platinum
    1. Newer drugs have 2 alkyl groups - bifunctional
      1. 2 groups can be pinned together by alkyl groups
      2. platinum compounds are also bifunctional
    2. e.g. Nitrogen/Sulphur mustard, Busulfan (alkylators)
    3. e.g. Cisplatin, Carboplatin (platinum compounds)
  3. Developed from mustard gas
  4. Has an effect on proliferating cells
    1. Activated inside the cell by loss of groups, generating reactive species
      1. Reactive species form adducts with biological molecules (especially Guanine)
      2. Inactivated inside cell by glutathione (GSH)
2. Antimetabolites
  1. Intefere with nucleotide synthesis and block DNA replication
    1. By targeting key enzymes involved in purine/pyrimidine bases
  2. Can be incorporated into DNA/RNA
    1. Causes DNA/RNA damage
      1. Bolus 5-fluorouracil is incorporated into RNA
      2. Intrafusional 5-FU is incorporated into DNA
        Often given as IV and bolus
        Now given as oral pro-drug Capecitabine
  3. e.g. purine analogues, pyrimidine analogues and antifolates
  4. Structure very similar to endogenous compounds
    1. e.g. 5-fluorouracil (similar to uracil) - becomes FdUMP when activated
      1. FdUMP inhibits thymidylate synthase (TS)
        Starves cells of dTTP - blocks DNA synthesis
        In normal cells Folate - dihydrofolate (FH2/folic acid) via dihydrofolate reductase
        FH2 - tetrahudrofolate (FH4) via DHFR
        FH4 is a methyl donor for deoxyuridine dUMP - dUTP (also regenerates FH2)
        In the presence of TS
    2. e.g. Methotrexate similar to folic acid (FH2)
      1. Folic acid is vital for synthesis of purines and thymidylate
      2. Methotrexate has a higher affinity for an enzyme than FH2
        Additional H/ionic bond formation
        FH4 depletion
        dTMP depletion
        Inhibition of DNA synthesis
      3. Taken up through folate transport system (resistance through decreased uptake)
      4. Metabolites (polyglutamate derivatives) can be retained for weeks/months
  5. Most active in S phase
  6. Have to be activated by enzyme systems, intra-cellularly
    1. Addition of sugar to make nucleosides
      1. Phosphorylation to nucleotide
        Incorporated into DNA/RNA
3. Topoisomerase inhibitors
  1. Cause DNA strand breaks and block Topoisomerase I and II involved in DNA winding/unwinding
    1. Stabilise Topo-DNA complex
  2. Topo I inhibitors - Irinotecan, Topotecan Topo
  3. Topo II inhibitors - Doxorubicin, Idarubicin, Etoposide
4. Tubulin acting drugs
  1. Block chromatin separation to daughter cells
  2. Vincas inhibit microtubule formation
  3. Taxabes promote microtubule formation
    1. Tubulin produces microtubules
      1. Form part of cytoskeleton
      2. Involved in cilia and flagella
      3. Part of neural axon
      4. Form spindle fibres during mitosis
  4. e.g. taxanes and vinca alkaloids
Resistance
1. Mechanisms of Drug Resistance
  1. Efflux pump
  2. Alterations in membrane lipids
  3. Compartmentalisation
  4. Decreased uptake
  5. Increased/altered drug targets
  6. Metabolism
  7. Altered cell cycle checkpoints
  8. Induction of emergency response genes - increased DNA repair, apoptosis inhibition
Cancer is caused by genetic lesions, leading to uncontrolled cell growth and loss of differentiation
1. Specific chromosomal translocations identified in some haematological malignancies
  1. Could switching off the gene cure cancer?
New Drug Targets
1. Target specific proteins that are altered/malfunctional in cancer cells
2. Evading apoptosis
  1. BCL-2
  2. NF-kB
  3. Heat-shock proteins
  4. Histone deactylases
3. Growth receptor signalling
  1. Receptor tyrosine kinases
  2. Signal transduction pathways
  3. Heat-shock proteins
  4. Histone deacetylases
4. Anti-growth signals
  1. TGF-beta targets
5. Limitless replication
  1. Telomerase insensitivity
6. Angiogenic/Metastatic Proteins
  1. VEGF
  2. Receptor tyrosine kinases
  3. Heat-shock proteins

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