chemo

• Cancer is the leading cause of death in Canada (1 in 4 deaths)

  
• There are over 100 types of cancers

  
• Cancer


  Characterized by abnormal cell growth with potential to spread to other parts of the body (metastasis)

  
• Causes of cancer


  • Environmental factors (tobacco, ionizing radiation, environmental pollution)
  • Genetic factors
  • Viral infections (HIV, Human Papiloma Virus)

  
• Cell cycle


  A series of events leading to duplication of DNA and division of cytoplasm to produce two daughter cells
• Cell cycle phases


  1. G1 phase (checkpoint to ensure cell ready for DNA synthesis)

  2. S phase (DNA synthesis)

  3. G2 phase (checkpoint to ensure cell ready for mitosis)

  4. M phase (mitotic phase - cell divides into two daughter cells)

  5. G0 phase (quiescent state)

  
• Tumor suppressor genes


  Genes (and the proteins they encode) that repress cell cycle or promote apoptosis

  
• Tumor suppressor genes


  • Inhibit cell division
  • Initiate apoptosis following irreversible DNA damage
  • Encode DNA repair proteins (BRCA)

  
• p53


  Tumor suppressor protein that regulates cell cycle

  
• p53 is mutated in 50% of all tumors
• Proto-oncogenes


  Normal genes involved in cell growth and proliferation or inhibition of apoptosis
• Oncogenes


  Mutated proto-oncogenes that increase expression and proliferation
• The Philadelphia chromosome is a specific genetic abnormality in chromosome 22 found in leukemia cancer cells. BCR is on chromsome 22, ABL on chromosome 9

  
• Philadelphia chromosome


  1. Abnormal translocation of chromosome 9 and 22

  2. Fusion creates a new gene BCR-ABL

  3. Leads to unregulated expression of protein tyrosine kinase activity (ABL gene) leading to unregulated cell cycle and cell division

  
• Usually multiple oncogenes and mutated tumor suppressor genes will all act in concert to cause cancer

  
• Cancer therapy


  • 1/3 cured with local treatment strategies (such as surgery or radiotherapy)
  • In remaining cases, systemic approach with anti-cancer drugs is required (because metastasis)
• Anti-cancer drugs alone cure less than 10% of all cancer patients when tumor is diagnosed at advanced stage (usually given in combination with surgery and radiation)
• Anti-cancer drugs


  Interfere with cell cycle

  
• Anti-cancer drugs


  • Some act at specific phases in the cell cycle, mainly at the S and M phase
  • Other drugs are cytotoxic at any point in the cell cycle

  
• Tumor cells generally have a higher percentage of proliferating cells than normal cells, so are more susceptible to S and M phase anti-cancer drugs

  
• Normal tissues that proliferate rapidly (bone marrow, hair follicles, an intestinal epithelium) are also susceptible to damage from cytotoxic drugs
• Few categories of medication have a narrower therapeutic index and greater potential for causing harmful effects than anti-cancer drugs
• Pyrimidine analogues (5-fluoro-uracil)


  Compete with normal pyrimidines precursors for the enzyme thymidylate synthase (TS), required for the conversion of dUMP to dTMP

  
• Purine analogues (6-mercaptopurine)


  Inhibit purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called phophoribosyl pyrophosphate amidotransferase (PRPP amidotransferase)

  
• Alkylating agents (Cisplatin)


  Highly reactive compounds which covalently link to chemical groups (phosphates, amines, sulfhydryl and hydroxyl groups) commonly found in nucleic acids, leading to cross-linking between strands of DNA and strand breakage
• Cancer cells are most susceptible to alkylating agents in late G1 and S phases of the cell cycle

  
• Anti-folates (Methotrexate targetting dihydrofolate reductase)


  Folic acid analogues that interfere with FH4 metabolism thereby inhibiting DNA replication
• Natural product anti-cancer drugs

  Compounds extracted from plants or bacteria with anti-cancer properties
• Natural product anti-cancer drugs

  • Vinca alkaloids
  • Taxanes
  • Epipodophyllotoxins
  • Camptothecins
• Vinca alkaloids

  Inhibit tubulin polymerization, disrupting the assembly of microtubules involved in mitotic spindle apparatus (M phase)
• Taxanes


  Promote microtubule assembly through high affinity binding, inhibiting mitosis and cell division (M phase) (Paclitaxel)
• Camptothecins


  Bind and stabilize the normally transient DNA–topoisomerase I complex, inhibiting the re-ligation step and leading to the accumulation of single-stranded breaks in DNA (S-phase specific)

  
• Anthracyclines


  Most widely used anti-cancer antibiotics, with 4 mechanisms of action: inhibit topoisomerases, generate free radicals, high affinity binding to DNA, and bind cellular membrane to alter fluidity and ion transport (Doxorubicin)
• Tyrosine kinase inhibitors (imantinib)


  Inhibit the tyrosine kinase domain of BCR-ABL oncoprotein- Treat leukaemia
• EGFR inhibitors


  Target the epidermal growth factor receptor, which is over-expressed in many solid tumors and promotes cell growth, proliferation, invasion, and metastasis, and angiogenesis
• Hormonal anti-cancer agents


  Block the binding of hormones to hormone-sensitive cancer cells

  
• Primary resistance


  Develops spontaneously in the absence of prior exposure to anti-cancer drugs (e.g. p53 mutations)

  
• Acquired resistance


  Develops in response to a given anticancer agent
• Adverse effects of anti-cancer drugs are dose-related and occur primarily in rapidly growing tissues, such as bone marrow, intestinal mucosa, and reproductive system

  
• Many anti-cancer drugs are carcinogenic in nature, thus increasing the risk of secondary malignancies