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
- 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
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