Systemic Anti cancer treatment Flashcards
What is chemotherapy?
- COMPOUND TARGETING DNA, RNA & PROTEINS - AIM IS TO FORCE CELLS INTO APOPTOSIS! - IT IS NON -SPECIFIC TO CANCER CELLS
*ALL RAPIDLY DIVIDING CELLS ARE AFFECTED *
How is chemotherapy delivered?
- IV & ORAL PREPARATIONS
- FREQUENCY OF ADMINISTRATION= CYCLES
- CYCLES DETERMINED BY PHARMACOKINETICS
- COMBINATION CHEMO - increased EFFICACY
- NEOADJUVANT (given before surgery)/ ADJUVANT (reduce risk of cancer returning)/ DISEASE CONTROL
PALLIATIVE(control disease for as long as possible)
What are the 3 main types of chemotherapy?
- Alkylating agents and platinum drugs - form DNA adducts
blocking DNA replication (all phases of cell cycle)
certain alkylating agents have ability to create cross links (changing structure of the DNA helix) and can act in all phases of cell cycle - Antimetabolites - structurally mimic essential molecules
required for cell division (S phase of cell cycle)
These may be incorporated into new nuclear material or bind irreversibly with vital enzymes for cell division - Organic drugs - vinca alkaloids / taxanes / anthracyclines
Give examples of organic drugs?
- Vinca alkaloids - bind to tubulin and prevent
microtubule assembly - which is essential for metaphase and mitosis - Taxanes - bins to beta tubulin subunit inhibiting
depolymerisation and disrupting mitotic spindle - Anthracyclines - microbial antibiotic targets
topoisomerase II (enzyme that releases torsional stress during the DNA replication)
Side effects of chemotherapy?
nausea and vomiting
Give examples of personalised systemic therapies?
- Hormonal Therapies - Anti - oestrogen, Aromatase
inhibitors - Targeted Therapies - EGFR, VEGF, CDK 4/6
- Immunotherapy - PD 1, PD -L1, CTLA - 4
Which hormones are linked to breast cancer?
Oestrogens (estradiol/esterone) play major role
Oestrogens promote cell proliferation within the breast tissue (higher rate of
cell division = more chances for mutations)
Prolonged exposure to oestrogen- increased RISK
What are breast cancer drugs?
Breast cancer drugs
Anti- oestrogen = Tamoxifen: Binds to the
oestrogen receptor and blocking oestrogen induced proliferation of cells
Aromatase inhibitors = Letrozole: Block
conversion to androgens to oestrogen
Describe how EGF works?
EGF binds to the tyrosine kinase receptor on cell membrane and this leads to receptor dimerization and autophosphorylation.
Following this there is activation of intracellular transducers including RAS pathway and transcription.
What have tyrosine kinase inhibitors been developed for?
to target tumours that express the EGF receptor
What stem cells is the immune system derived from?
haematopoietic stem cells
What do B cells do?
produce tumour specific antibodies- induce cell lysis and ultimately death
What do T cells do?
helper T cell vs cytotoxic t cells - kill cells
What are immune checkpoints for?
to ensure that self tolerance is maintained
What are immune checkpoints activated by?
Activated by receptor ligand
binding (PD-1 to PD-L1)
(CTLA-4 to B7)
What do immune checkpoint inhibitors do?
(PD1 PDL1 AND CTLA-4)
removal of the brakes of the
immune system allowing
increased T cell activity
What are cyclic kinases and cyclin dependent kinases responsible for?
movement of cells through cell cycle
What does cyclin D along with CDK4/6 responsible for?
helps to move cells from the G0 resting phase into G1 to begin growth
production of cyclin d regulates cyclin e - which controls passage into s phase
Immunotherapy side effects?
- Colitis - most common - 30% develop diarrhoea of any grade and
10% have severe grade 3-4 in dual IO.10 - Pneumonitis - more common in PD-L1 treatment reference 11
- Hypophysitis/ Thyroid dysfunction/ Diabetes - 5-10% develop
endocrine adverse events reference 12 - Hepatitis - occurs <5% 11
- Dermatitis - most frequent toxicity for PD-L1 and CTLA-4 11
- Nephritis - <1 % 11
- Neurological <0.2% 11
What are side effects of EGF receptor inhibitors?
not entirely specific and still cause disruption to normal cells.
Resulting in side effects such as diarrhoea, dry skin, rash , hypertension and deranged liver function.
What does the inhibitor ,palbociclib, do?
block the progression of cells through cell cycle in metastatic breast cancer
What are the descendents of stem cells called?
progenitor cells
What are progenitor cells divided into?
myeloid or lymphoid
Which cells respond early?
neutrophils and NK cells
What cells respond later?
B and T cells -adaptive immune response
How do PD-1 inhibitors drive killing of cancer cells by t cells?
PD-1 found on T cells binds to another protein called PD-L1 helping to keep T cells from killing other cells including cancer cells.
PD-1 inhibitors block binding to PD-L1 and this means the brakes on immune system are released and t cells can kill cancer cells.
What is pembrolizumab? (KEYTRUDA)
selective humanised IgG4 monoclonal antibody targeted at the PD-1 checkpoint
blocks PD-1 receptors from binding to immune dampening PD-1 and PD-2 ligands in the tumour
