Principles of Chemotherapy

Principles of Chemotherapy

1. Gets to tumour via bloodstream

   • Reaches primary tumour and metastases

2. Kills cells by apoptosis

   • Has some toxicity to heathly cells
     • Due to therapeutic window - gap between efficacy and toxicity

3. Combinations of chemotherapeutic drugs given in cycles

   • Treatment 1 is strong to reduce tumour size before surgery, irradiation and multiple course chemotherapy
     • Treatment 2 is used to eliminate micrometastatic disease

4. Immunotherapy - Can be used to guide imaging of tumour

5. Drug examples

   • Pentostatin - inhibits adenosine deaminase
   • 6-Mercaptopurine and 6-Tioguanine - inhibit purine synthesis and nucleotide interconversions
   • Methotrexate - inhibits purine and DTMP synthesis
   • Cytarabine - inhibits DNA polymerase and RNA function
   • Crisantaspase - deaminates asparagine and inhibits protein synthesis
   • 5-Fluorouracil - inhibits DTMP synthesis
   • Bleomycins - damage DNA and prevent repair
   • Alkylating agents, Mytomycin and Cisplatin - cross-link DNA
   • Campothecins, Doxorubicin, Etoposide and Amsacrine - inhibit RNA synthesis and topoisomerase II
   • Dactinomycin - intercalates in DNA, inhibits topoisomerase II and RNA synthesis
   • Vinca Alkaloids and Taxanes - inhibit function of microtubules

6. Major Classes of Cytotoxics

   • DNA binding drugs
     • Cause direct DNA damage and block DNA replication
     • e.g. alkylating agents and platinum
       • Newer drugs have 2 alkyl groups - bifunctional
         • 2 groups can be pinned together by alkyl groups
         • platinum compounds are also bifunctional
       • e.g. Nitrogen/Sulphur mustard, Busulfan (alkylators)
       • e.g. Cisplatin, Carboplatin (platinum compounds)
     • Developed from mustard gas
     • Has an effect on proliferating cells
       • Activated inside the cell by loss of groups, generating reactive species
         • Reactive species form adducts with biological molecules (especially Guanine)
         • Inactivated inside cell by glutathione (GSH)
   • Antimetabolites
     • Intefere with nucleotide synthesis and block DNA replication
       • By targeting key enzymes involved in purine/pyrimidine bases
     • Can be incorporated into DNA/RNA
       • Causes DNA/RNA damage
         • Bolus 5-fluorouracil is incorporated into RNA
         • Intrafusional 5-FU is incorporated into DNA
           • Often given as IV and bolus
             • Now given as oral pro-drug Capecitabine
     • e.g. purine analogues, pyrimidine analogues and antifolates
     • Structure very similar to endogenous compounds
       • e.g. 5-fluorouracil (similar to uracil) - becomes FdUMP when activated
         • 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
       • e.g. Methotrexate similar to folic acid (FH2)
         • Folic acid is vital for synthesis of purines and thymidylate
         • Methotrexate has a higher affinity for an enzyme than FH2
           • Additional H/ionic bond formation
           • FH4 depletion
             • dTMP depletion
               • Inhibition of DNA synthesis
         • Taken up through folate transport system (resistance through decreased uptake)
         • Metabolites (polyglutamate derivatives) can be retained for weeks/months
     • Most active in S phase
     • Have to be activated by enzyme systems, intra-cellularly
       • Addition of sugar to make nucleosides
         • Phosphorylation to nucleotide
           • Incorporated into DNA/RNA
   • Topoisomerase inhibitors
     • Cause DNA strand breaks and block Topoisomerase I and II involved in DNA winding/unwinding
       • Stabilise Topo-DNA complex
     • Topo I inhibitors - Irinotecan, Topotecan Topo
     • Topo II inhibitors - Doxorubicin, Idarubicin, Etoposide
   • Tubulin acting drugs
     • Block chromatin separation to daughter cells
     • Vincas inhibit microtubule formation
     • Taxabes promote microtubule formation
       • Tubulin produces microtubules
         • Form part of cytoskeleton
         • Involved in cilia and flagella
         • Part of neural axon
         • Form spindle fibres during mitosis
     • e.g. taxanes and vinca alkaloids

7. Resistance

   • Mechanisms of Drug Resistance
     • Efflux pump
     • Alterations in membrane lipids
     • Compartmentalisation
     • Decreased uptake
     • Increased/altered drug targets
     • Metabolism
     • Altered cell cycle checkpoints
     • Induction of emergency response genes - increased DNA repair, apoptosis inhibition

8. Cancer is caused by genetic lesions, leading to uncontrolled cell growth and loss of differentiation

   • Specific chromosomal translocations identified in some haematological malignancies
     • Could switching off the gene cure cancer?

9. New Drug Targets

   • Target specific proteins that are altered/malfunctional in cancer cells
   • Evading apoptosis
     • BCL-2
     • NF-kB
     • Heat-shock proteins
     • Histone deactylases
   • Growth receptor signalling
     • Receptor tyrosine kinases
     • Signal transduction pathways
     • Heat-shock proteins
     • Histone deacetylases
   • Anti-growth signals
     • TGF-beta targets
   • Limitless replication
     • Telomerase insensitivity
   • Angiogenic/Metastatic Proteins
     • VEGF
     • Receptor tyrosine kinases
     • Heat-shock proteins