10.2 Pharmacological treatment of cancer Flashcards
Why is surgery alone not always sufficient when treating cancers?
Surgery is the most effective treatment but come cancers are inoperable:
- Cancer is too big or has metastasised
- Inaccessible
- Too close to vital blood vessels/organs
- Patient is not fit enough
- Blood cancers
What type of drugs are used in chemotherapy?
Cytotoxic drugs (prevent cell growth or replication)
What type of cancer is a carcinoma?
Carcinoma = cancer that forms in epithlial tissue
Describe the developent of a carcinoma.
- Begins with hyperplasia of epithelial cells
- Cells surrounding tumour undergo apoptosis
- Cancer cells survive for considerable lengths of time, at this point it is called a carcinoma in situ
- When the cancer breaks through the basement membrane, the tumour is malignant and the cancer is serious and could metastasise
What are the hallmarks of cancer cells?
ARIES+E
- Inducing Angiogenesis
- Resisting cell death
- Invasion and metastasis
- Evading growth suppressors
- Sustaining prolif signalling
- Enabling replicative immortality
GTA+D
- Genome instability and mutation
- Tumour-promoting inflammation
- Avoiding immune destruction
- Deregulating cellular energetics/metabolism
What are the 3 principles of cytotoxic chemotherapy?
- Cytotoxic chemotherapeutic agents lack sepcificity, they target a process of the cell (proliferation)
- Some cytotoxic agents are cell cycle phase specific (e.g. some target DNA transcription, some target metabolic sites for DNA synthesis)
- Cytotoxicity is proportional to the total drug exposure (area under concentration/time curve)
What type of cells do cytotoxic chemo agents target?
Cells that are actively progressing through the cell cycle.
Only target proliferating cells.
Cannot target cells in G0 phase (quiescent).
For those cytotoxic agents that are cell cycle phase specific, what considerations must be made?
The agent must be circulating within the body for a longer period of time to be successful. Duration is important.
Explain why the area under the concentration/time curve for cytotoxic drugs is important.
Indicates the total drug exposure.
What type of growth kinetics do cancer cells exhibit?
Gompertzian growth kinetics.
NOT exponential growth.
Explain Gompertzian growth kinetics.
- When the tumour begins to grow, it does so slowly
- It requires an accumulation of genetic changes to start proliferating rapidly
- Then undergoes exponential growth until it reaches 10^9 number of cells
- Growth tails off, this is the point where scanning modalities will detect tumours
- Diagnosis therefore is relatively late
Describe the nutritional supply to cancer cells.
- When tumour is small, nutrients are received from BVs at the tumour surface
- As the tumour grows, the cells at the centre cannot receive nutrients and die
- There is a proportion of cells inbetween that have insufficient nutrient supply to grow, but insufficient to progress through the cell cycle (they remain in phase G0 and are resistant to cytotoxic chemotherapy as they’re not actively progressing through the cell cycle).
What is the log kill hypothesis?
Aka. fractional kill hypothesis.
- Delivering cytotoxic chemo agents in cycles to reveal the G0 cells, allowing them to receive nutrients and re-enter the cell cycle to then redeliver chemotherapy
Should cancer be treated using a single drug or several?
Should use combination therapy.
- Cancer is a heterogenous disease and there is potential for resistant populations
- Range of cytotoxic agents with a hope that each agent will target a subpopulation of cells in the tumour
- Up to 4 or 5 therapeutic drugs can be used at one time
What is meant when we say cancer is a heterogenous disease?
- Lots of different cell types involved and incorporated into tumours
- Not just epithelial cells, e.g. immune cells, stromal cells
What are the requirements for cytotoxic drugs used in combination?
- Must be highly effective as single agents, killing at least 99% of a cell type or more
- Must have individual mechanisms of action
- Have non-overlapping toxicity (challenging)
Name the major cytotoxic drug groups and examples of drugs.
- Alkylating agents (procarbazine, cyclophosphamide)
- Anti-metabolites (methotrexate)
- Cytotoxic antibiotics (doxorubicin)
- Plant derivatives (vinca alkaloids)
- Miscellaneous agents (bleomycin)
Why is cytotoxic chemotherapy only delivered in 3-6 month periods?
Due to the severe side effects. Treatment can only be provided over a limited period of time.
Intermittent therapy is also used (cycles of treatment to exploit differences in grwoth fraction between normal and malignant cells).
What are the possible oral complications common to cytotoxic chemotherapy?
Why is a thorough oral evaluation prior to cancer treatment necessary?
