Lesson 5 Classes of Chemotherapy, Identifying cancer drugs

• Chemotherapy drugs primarily target dividing cells. Different classes act at different stages of cell cycle
• Topoisomerase inhibitors


  Prevent resolution of kinks in DNA during replication
• Anti-metabolites


  Interfere with DNA synthesis
• Microtubule inhibitors


  Prevent proper segregation of chromosomes during mitosis
• Alkylating agents


  Create lesions in DNA that create breaks during replication
• Chemotherapy can be described as: Cut, burn and poison
• Autopsies of mustard gas victims: substantially lower numbers of lymphoid, myeloid cells
• US Department of Defense pharmacologists reasoned: if it could kill normal haemopoietic cells, perhaps it could kill cancerous ones
• Nitrogen mustards (such as cyclophosphamide)

  • They act by alkylating DNA
  • DNA damage detected and apoptosis induced
  • Crosslinking and fragmentation during attempted DNA repair
• Anti-metabolite drugs (eg methotrexate)


  • They interfere with DNA and RNA synthesis by substituting for normal nucleotides, or preventing their production
  • Drug-induced nucleotide deficiencies or substitution lead to DNA breaks, apoptosis
  • They act primarily in S phase of the cell cycle
• Methotrexate is an example of an antimetabolite used today for anti-cancer therapy
• Topoisomerase inhibitors (eg doxorubicin)

  • Strands of DNA double helix must be separated for replication (or transcription). This creates torsional strain. Topoisomerases relieve this strain by cutting and rejoining DNA.
  • Topoisomerase inhibitor eg doxorubicin prevents rejoining of cut DNA: leading to DNA breaks and apoptosis
• Paclitaxel: from bark of the scarce Pacific yew (Taxus brevifolia)


  1967
• Very inefficient: trees endangered and ecosystem threatened (entire tree population on earth < one decade's supply)
• Now: alternative source: semisynthetic process makes paclitaxel and docetaxel, from abundant precursor from the needles of more plentiful European yew (Taxus baccata)
• Microtubule inhibitors (eg paclitaxel)

  • Microtubules are cytoskeletal structures which are composed of tubulin monomers
  • Microtubules are dynamic: monomers are added to the "+" end and removed from the "-" end
  • Important in spindle formation, mitosis
• Taxanes


  Microtubule stabilising drugs
• Mechanism of toxicity of taxanes

  • Microtubule depolymerisation/ shortening pulls sister chromatids apart to opposite poles of the cell
  • Taxanes like paclitaxel stabilise microtubules by reducing depolymerisation, preventing shortening
  • This stops segregation of chromosomes at mitosis, stopping cell division ("cytostatic")
  • It can also lead to DNA damage which provokes apoptosis ("cytotoxic")
• National Cancer Institute (USA) Developmental Therapeutics Program

  • 400,000 drugs in repository
  • 80,000 have been screened using current process
• Sources of drugs


  • Government laboratories
  • Research institutes
  • Universities (60%)
  • Companies (40%)
• Approximately one half of the chemotherapeutic drugs currently used by oncologists for cancer treatment were discovered and/or developed at NCI
• Screening process


  • In vitro responses of 3 tumour cell lines
  • In vitro responses of 60 tumour cell lines
  • Activity against tumour cells implanted into mice
  • Pharmacology
  • Toxicology in 2 animal species
  • Phase I clinical trials (safety in humans)
• Clinical trial phases


  • Phase 0: Pre-clinical (animal, in vitro etc)
  • Phase I: Evaluates how a new drug should be given (orally, injected etc), how often, and what dose is safe ("maximum tolerated dose"), pharmacology
  • Phase II: Continues to test safety, and begins to evaluate how well the drug works. Usually focus on a particular cancer
  • Phase III: These studies compare a new drug (or combination of drugs), to the current standard. Usually randomised controlled trials
  • Phase IV: To evaluate the side effects, risks, and benefits of a drug over a longer period of time and in a larger number of people, after a treatment has been approved and is being marketed
• National Cancer Institute's perspective on risk and investment
• Topoisomerase: a nuclear enzyme which alters the supercoiled form of a DNA molecule, which ultimately reduces strain (untangles DNA)
• Doxorubicin

  Adverse effects: cardiotoxic


  Topoisomerase Inhibitor
• Cyclophosphamide: a synthetic cytotoxic drug, works as a alkylating agent
• Describe the goals and scale of phase I, II, III & IV

  Phase 0: Pre-clinical (animal and in vitro) - No Participants

  Phase I: Evaluates the safe dose and how drugs are administered - 10-30

  Phase II: Continues to test safety, and begins to evaluate how well the drugs work - <100

  Phase III: Compare the drugs to current standard, Focus on a particular cancer - 100-300

  Phase IV: Evaluate the side effects, risks and benefits of a drug over a longer period of time - 500-5000