D14 - treating cancer Flashcards
1
Q
Terminology
A
- Cancer - hundreds of types and subtypes
- All cancers are characterised by
○ Genetically altered cells
○ Uncontrolled proliferation - Uncontrolled proliferation
○ Several contributing mechanisms
○ But not necessarily malignant - Malignant - tumour invades local tissues
Metastatic - malignant cells spread via blood or lymph to colonise distant organs
- All cancers are characterised by
2
Q
Origins of cancer mutations
A
- The great majority of cancer mutations are sporadic ie. 2 degree to external factors and bad luck and not inherited
- Environmental external (genotoxic) factors:
○ UV irradiation - melanoma
○ Smoking - lung and other cancers
○ Asbestos - mesothelioma (tumour of the lining of the plural cavity)
○ Benzene - leukaemia - Cancers take a long time to develop
○ Increased age is associated with increased cancer rates
Mutations accumulate over time
- Environmental external (genotoxic) factors:
3
Q
Stepwise mutations and caner
A
- Tumour cells accumulate a number of mutations (capabilities) to evade normal checks and balances on cell growth, division, death and movement
- Mutations occur in a limited number of key genes
- At least 8 new capabilities are required for cancer cells to develop into malignant tumours
- Produce own growth signals
- Deaf to signals telling them not to divide
- Evade apoptosis
- Become immortal
- Develop own blood supply
- Become invasive metastasis
- Metabolic energy changes
- Block the immune response
4
Q
8 new capabilities are required for cancer cells
A
- Produce own growth signals
2. Deaf to signals telling them not to divide
3. Evade apoptosis
4. Become immortal
5. Develop own blood supply
6. Become invasive metastasis
7. Metabolic energy changes
8. Block the immune response
5
Q
Evolution of cancer treatments
A
- Originally surgical - excision or debulking
- Radiotherapy - first used in the 1950s
- Chemotherapy drugs - developed in 1940-70s
- Biological therapies - B/M transplants, G-CSF etc.
- Targeted therapies - since 1990s
6
Q
Early history of chemotherapy
A
- Mustard gas in WW1 - autopsies revealed myelosuppression and lymphoid hypoplasia
- WW2 bombing of Allied ships in Italy - mustard gas was released - survivors had severe myelosuppression
- Nitrogen mustard therefore developed to treat lymphoid malignancies
- Folic acid - low in megaloblastic anaemia so used to treat ALL
○ Increased proliferation - Folate analogues (anti-folates) synthesised - ALL remission
7
Q
Classical chemotherapy drugs
A
- Cancer cells proliferate uncontrollably - DNA replication is crucial to growing number of tumour cells
- Traditional anticancer drugs target growing cells
- Many interfere with DNA synthesis and/or function via
○ Chemical damage to DNA - adducts or cross linking
○ Impaired DNA base synthesis - purines and pyrimidines
○ Inhibition of transcription - Other mechanisms include inhibition of
○ Translation
○ Mitosis
8
Q
major classes of chemotherapy drugs
A
alkylating agents, anti-metabolites, mitotic inhibitors
9
Q
Alkylating agents
A
- Oldest class of chemotherapy agents - classical alkylating drugs eg. Cyclophosphamide
- Also includes newer platinum drugs eg. Cisplatin
- Alkylate (methyl/ethyl) DNA at guanine bases to form DNA adducts or DNA strand crosslinks
- Base excision repair of guanine adducts leads to strand breaks
- Cross linked DNA cannot be replicated or transcribed
10
Q
Anti-metabolites
A
- Deprive cells of building blocks required for DNA synthesis
- Two main groups
§ Folic acid antagonists - block dihydrofolate reductase (DHFR) to deplete cellular folate needed for purine synthesis eg. Methotrexate
§ DNA base analogues - pyrimidine, purine, and nucleoside analogues, eg. 5FU, 6-mercaptopurine
11
Q
Mitotic Inhibitors
A
- Interfere with mitotic spindle through effects on microtubules
- Two main groups
§ Vinca alkaloids
□ Bind tubulin to prevent MT polymerisation, eg. Vincristine
§ Taxanes
□ Bind MTs to prevent their disassembly eg. Paclitaxel
12
Q
Side effects of chemotherapy drugs
A
- Systemic agents - systemic effects
§ GI - mouth ulcers, nausea and vomiting, diarrhoea
§ Hair loss - severe with alkylating agents
§ Myelosuppression - infections (decrease WBCs), anaemia (decrease RBC) and bruising (decreased platelets)
§ Drug specific effects
13
Q
5 year survival rates in paediatric cancer
A
- Although classical chemotherapy has severe side effects
- Survival rates have increases in many cancers especially paediatric cancers, leukaemias and lymphomas
- Eg. Paediatric ALL
14
Q
Combination chemotherapy
A
- Rationale - maximise tumour cell kill by
- Different modes of action - eg. Alkylating + anti-metabolite
- Action at different times on the cell cycle
- Synergistic effects
- Dissimilar toxic effects on cancer cells - allows lower doses
15
Q
Targeted therapies
A
- Inhibit oncogene-driven cancer signalling pathways
- Receptor tyrosine kinases- Inhibitors - target specific proteins via 2 mechanisms
- Antibodies - humanised proteins, extracellular (-abs)
- Small molecule inhibitors - membrane permeable, target kinase domains in the intracellular space (-ibs)
- Switch off proliferation and survival signalling
- Inhibitors - target specific proteins via 2 mechanisms
