What are the potential ways that tumours can spread?
What is local spread of cancer?
Direct involvement of surrounding structures
What cancers spread via the lymphatics?
What cancers spread via the blood?
- Later stage carcinomas
What happens in implantation spread of cancer?
There is mechanical spread of detatched clumps of tumour cells to the peritoneum, ureters, or CSF
What are the treatment options for cancer?
- Biologically targetted therapy
In what ways can chemotherapy be used in treating cancer?
- Radical primary treatment
- Adjuvant therapy
- Neoadjuvant therapy
- Palliative care in advanced disease
Where is chemotherapy used as a radical primary treatment?
In haemotological malignancies, such as lymphomas and leukaemias
What is the definition of adjuvant chemotherapy?
Post-operative treatment in a patient at high risk of microscopic metastases after the removal of the primary tumour
What is neoadjuvant chemotherapy?
Primary treatment of patients with clinically localised tumour - use chemotherapy upfront to improve the outcome of the primary therapy
What are the advantages of neoadjuvant chemotherapy?
- Can assess the biological responsiveness of the tumour
- May allow for conservation surgery
- May achieve pCR (pathological complete response
What determines the rate of tumour growth?
- Growth fraction
- Duration of cell cycle
- Rate of cell loss
What does topoisomerase 1 do?
It causes transient single strand cleavage, relaxes the strand, and then sticks it back together
How does topoisomerase 1 inhibition work?
You get binding to the TOPO 1-DNA complex, without affecting the cleavage region. This means that the enzyme cannot rejoin the DNA, resulting in a double stranded break and therefore cell apoptosis
What is the advantage of a unique tumour-activated agent?
It wouldn't affect normal tissue, and so minimises side effects
Give an example of a tumour activated chemotherapy agent?
What is the mechanism of action of xeloda?
- It is absorbed in the intestine
- It is converted to 5'-DFCR CyD and then 5'-DFUR
- 5'-DFCR CyD and 5'-DFUR are transported into the tumour tissue, where they are converted to 5-FU
- 5-FU blocks DNA replication
What happens to spindle microtubules once chromosomes are aligned at the metaphase plate?
They depolymerise, moving sister chromatids towards opposite poles
How do micro-tubule binding agents affect microtubule dynamics?
- Inhibit polymerisation
- Stimulate polymerisation and prevent depolymerisation
What does it need to be ensured if combination therapy is to improve activity?
- Drugs have a different mechanism of action
- Drugs have different mechanisms of resistance
What needs to be ensured if combination therapy is to be safe?
They have compatible side effects
What is P-glycoprotein?
An ATP-powered efflux pump
What does P-glycoprotein do?
Pumps cytotoxic agents out of the cells against the concentration gradient
What repair pathway is employed in single-stand breaks?
Base excision repair
What enzyme is used in base excision repair?
What repair pathway is employed in double stranded DNA breaks?
What enzymes are used in recombinational repair?
- ATM in homologous recombination repair
- DNA-PK in non-homologous end joining
What repair pathway is employed when bulky adducts are added to DNA?
What enzymes are used in nucleotide-excision repair?
What repair pathway is employed with insertions and deletions to DNA?
What repair pathway is employed with O6-alkylguanine DNA damage?
What enzyme is involved in direct reversal of O6-alkylguanine mutations?
Give the process of repair of single strand DNA breaks by PARP-1
- PARP binds directly to single strand breaks
- Once bound to damaged DNA, PARP modifies itself producing large branches chains or PAR
- PAR recruits repair enzymes, which fix the break
- PAR chains are degraded via PARG
What effect does inhibiting PARP-1 have on DNA?
It increases double stranded DNA breaks, as it prevents recruitment of repair factors to repair SSB, which then progress to DSB after S-phase of DNA replication
Give an example of a homologous recombination repair deficient cell
Cells with BRCA 1 or 2 mutations
How does olaparib work in BRCA-deficient cancer cells?
It causes double strand breaks, which can be repaired effectively by HR pathways in normal cells, allowing them to survive, but kills cancer cells as they don't have the pathway to repair
Give two examples of hormones that can be carcinogenic
- Oestrogen in breast cancer
- Testosterone in prostate cancer
What is important when considering carcinogenic hormones?
Prolonged exposure, e.g. in the case of breast cancer, should consider age of menarche, age of first pregnancy etc
What are the categories of endocrine therapies for breast cancer?
- Aromatase inhibitors
- LHRH agonists
Give an example of an anti-oestrogen breat cancer therapy
Give 5 examples of aromatase inhibitors
Where do aromatase inhibitors have a particular use?
When women are post menopausal
Why do aromatase inhibitors have a particular role when women are post-menopausal?
Because they are reliant on the aromatase enzyme to produce any oestrogen
Doesn't work in pre-menopausal women, as they are producing their own ovarian oestrogen
Give an example of a progtesterone therapy for breast cancer
Give an example of a LHRH agonist
What are the categories of endocrine therapies for prostate cancer?
Give 3 examples of anti-androgens
- Cytoproterone acetate
Give an example of an oestrogen therapy for prostate cancer
How does giving oestrogen help in prostate cancer?
It compensates for the testosterone drive for prostate cancer
Give an example of a novel endocrine agent used in the treatment of prostate cancer
What is the mechanism of action of abiraterone?
It inhibits the crucial CYP17A1 enzyme, which is needed for the conversion of pregnenolone and progesterone to testosterone