Lesson 6 Chemotherapy Limitations

• Some cancer cells express enzymes that remove alkyl groups from DNA, conferring resistance to alkylating agents
• Drugs that are inactivated, Pro-drugs that are activated by cytochrome P450


  • Cyclophosphamide
  • Dacarbazine
  • Docetaxel
  • Etoposide
  • Exemestane
  • Flutamide
  • Fulvestrant
  • Gefitinib
  • Idarubicin
  • Ifosfamide
  • Imatinib
  • Irinotecan
  • Letrozole
  • Mitoxantrone
  • Paclitaxel
  • Procarbazine
  • Tamoxifen
  • Tegafur
  • Teniposide
  • Thiotepa
  • Topotecan
  • Toremifene
  • Vinblastine
  • Vincristine
  • Vindesine
  • Vinorelbine
• Cancer types treated with those agents
• Efflux pumps


  MDR1 pumps certain chemicals out of cells, high level expression of this efflux pump can render cancer cells cross-resistant to many anti-cancer drugs, MDR1 also confers resistance to drugs used to treat other conditions
• Chemotherapy treatments tend not to eliminate quiescent cancer stem cells, which can then regenerate the tumour once the treatment stops
• Only a subpopulation of cells in tumours have the capacity for limitless self-renewal, these are quiescent (non-dividing): cancer stem cells

  
• Chemotherapy drugs are most effective when the drug can easily access the tumour, most drugs only penetrate 150 µm from vessels
• Blood-brain barrier tends to limit drug accessibility to brain tumours (even though vessels in tumours tends to be more leaky than in normal brain)
• Non-systemic delivery to increase local chemotherapy concentration

  Intratumoural administration or delivery into tumour cavity
• Although the remissions provoked by agents including nitrogen mustard derivatives, anti-folates and taxanes were encouraging, most patients relapsed and died
• Presumably a subpopulation of cells within the tumours was resistant to the drug and treatment selected for their survival, then proliferation led to recurrence

  
• By analogy with combination antibiotics for bacterial diseases, oncologists tried combining agents from different classes of drugs, significant toxicity but better cure rates
• Other oncologists experimented with increasingly complex combinations
• In late 1960s, oncologists gave children with leukaemia "total chemotherapy": five agents plus radiotherapy, combination did improve survival!

  
• Adding additional treatments and refining doses and timing further boosted cure rates
• Childhood acute leukaemia now has one of the best prognoses of any cancer

  
• Chemotherapy drugs are poisons that primarily target dividing cells
• Even combination chemotherapy regimens cannot cure some cancers
• Other dividing cells are also killed, including immune cells which might otherwise help eliminate the cancer and counter infections, gut cells that maintain nutrition etc etc
• Some drugs are particularly toxic to specific organs (eg doxorubicin to cardiomyocytes)
• Therapeutic window/index

  Defines the dose range that balances maximising efficacy while avoiding intolerable adverse effects

  
• Acute side effects of chemotherapy

  • Immune system impairment, infections
  • Anaemia, fatigue
  • Nausea, vomiting, diarrhoea or constipation, malnutrition, dehydration
  • Hepatotoxicity (liver damage)
  • Nephrotoxicity (kidney damage)
  • Ototoxicity (inner ear damage): vertigo, hearing loss
  • Cardiotoxicity (heart damage)
• Late side effects of chemotherapy (years after therapy)

  • Heart muscle damage, congestive heart failure
  • Thickening of the lining of the lungs, inflammation of the lungs, difficulty breathing
  • Ovary damage: premature menopause, sexual dysfunction, osteoporosis. Infertility (both sexes)
  • Hearing loss
  • Learning, memory, and attention difficulties
  • Digestive and liver problems
  • New primary cancers (from damage to DNA in non-cancerous cells)
• Some of these toxicities can be fatal
• Chemotherapy and radiotherapy can cause mutations that can be oncogenic
• Risk adapted therapies for childhood acute lymphocytic leukaemia

  • Previously, any sub-lethal toxicity was acceptable as long as treatments eliminated the cancer
  • Now, priorities have shifted towards minimising toxicities while maintaining efficacy
• Factors used to stratify patients into distinct risk groups

  1. Abundance of leukaemia cells in blood, bone marrow, cerebrospinal fluid

  2. Determination of leukaemia type

  3. Presence/absence of chromosomal translocations

  4. Response to initial (induction) treatment
• Patients with relatively good prognosis are given less intense, less toxic, therapy
• Patients with poorer prognosis are given more intense, more toxic treatment
• Enhanced Permeability and Retention (EPR) effect


  Neo-angiogenesis creates abnormally structured leaky vessels in tumours, allowing nanoparticles loaded with chemotherapy drugs to accumulate in tumours more than normal tissues
• Most cancer patients still treated according to "cut, burn and poison"
• Traditional chemotherapy drugs and radiotherapy damage DNA, tend to be more toxic to dividing than quiescent cells, and hence are somewhat selective for cancer cells
• These treatments can be quite effective, but sometimes they don't work and they often cause severe (sometimes lethal) adverse effects due to impact on normal cells
• Researchers are working to enhance the efficacy and reduce the toxicity of chemotherapy, and to develop targeted therapies that target molecular features of cancer cells