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Chemotherapy

  • Aims of chemotherapy are to selectively destroy tumour cells
  • Achieved by specific growth characteristics of  most tumours

Cell cycle

  • A cells synthesising DNA go through a regular cycle with different phases

Cell cycle

  • G0 is a resting phase outside the cell cycle
  • Cells is G0 are resistant to the effects of cytotoxic drugs

Mechanism of action

  • The faster cells are growing the more likely that cytotoxic drugs are to 'catch' them
  • Also accounts for toxicity on rapidly growing normal tissues (e.g. GI mucosa, bone marrow)
  • Large tumours are relatively unresponsive to chemotherapy
  • More cells are in G0 and drug penetration is less reliable
  • Most drugs kill a fixed proportion of cells rather than fixed number
  • Different drugs act at different phases of the cell cycle
  • As a result, combinations of drugs are more likely to be effective
  • Modes of action include:
    • Bleomycin - inhibits DNA polymerase causing breakage of single stranded DNA
    • Doxorubicin - Inhibits RNA synthesis by intercalating between DNA base pairs
    • Cisplatin - inhibits DNA synthesis by cross-linking DNA strands
    • Methotrexate - inhibits dihydrofolate reductase
    • Vinca alkaloids - binds to tubulin and inhibits the metaphase of mitosis

Non-phase dependent drugs

  • Kill cells exponentially with increasing dose
  • Equally toxic for cell within the cell cycle or G0 phase
  • Examples include:
    • Alkylating agents - cyclophosphamide, cisplatin
    • 5-Flurouracil
    • Anthracyclines - doxorubicin

Phase dependent drugs

  • Kill cells at a lower dose
  • Act within a specific phase of the cell cycle
  • Examples include:
    • Methotrexate
    • Vinca alkaloids - vincristine, vinblastine

General side effects

  • Some side effects occur with many cytotoxic agents
  • These include:
    • Nausea and vomiting
    • Bone marrow toxicity
    • Gastrointestinal toxicity
    • Alopecia
    • Gonadal effects
    • Hyperuricaemia

Specific side effects

  • Some side effects are specific to certain agents
  • These include:
    • Pulmonary fibrosis - bleomycin
    • Haemorrhagic cystitis - cyclophosphamide
    • Cardiomyopathy - doxorubicin
    • Hepatic damage - methotrexate
    • Skin pigmentation - 5-flurouracil

Tumours potentially curable with chemotherapy

  • Acute lymphoblastic leukaemia
  • Germ cell tumours
  • Choriocarcinoma
  • Hodgkin's disease
  • Wilm's tumour

Tumours with a significant response to chemotherapy

  • Breast carcinoma
  • Ovarian carcinoma
  • Lymphoma
  • Osteosarcoma

Tumours poorly responsive to chemotherapy

  • Pancreatic carcinoma
  • Melanoma
  • Soft tissue sarcomas
  • Colorectal carcinoma
  • Gastric carcinoma

Bibliography

 

 
 

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