Lectures 9, 10 + 11 - Radiotherapy, Chemotherapy and Chemoprevention Flashcards
What are the 2 major aims of radiotherapy?
Maximise the dose to the tumour whilst minimising the effect to local tissues
What are the 3 types of radiotherapy?
- External beam
- Brachytherapy
- Unsealed sources
Briefly outline the mechanism of action of radiotherapy at the atomic level
Compton process:
- High energy photon interacts with loosely bound free electrons
- Part of the photon’s energy is given to the electron as KE
- The photon is then deflected - proceeds with lower energy
Net result is “fast” electrons and a deflected electron of lower energy
What is the name of the process which occurs at the atomic level in diagnostic radiology?
Photoelectric process
Outline the photoelectric process
- Low energy photon interacts with tightly bound electrons
- Photon gives up all its energy
- Electron is ejected - now fast
Net result is fast electrons and photon energy entirely absorbed - does not proceed
How do the Compton and photoelectric processes differ in terms of absorption?
Compton - independent of atomic number - penetrates all tissue types - reaches target
Photoelectric - absorption varies depending on atomic number - differentially absorbed by different tissues
Outline the mechanism of action of radiation at the molecular level
May be direct or indirect:
- Direct - directly ionises DNA
- Indirect - interacts with molecules which then produce free radicals which ionise DNA
Describe the distribution of energy release with ionising radiation
Not uniformly released - deposited randomly in discrete regions of concentrated energy
Hence not actually a lot of energy, just highly conc
What is the unit of ionising radiation?
What does 1 of them equate to?
Gray (Gy)
1 Gy = 1 Joule per kg
How does radiation lead to mutations?
Damages DNA - in particular causes double-strand breaks - either kills cell, or leads to misrepair –> mutation
What is fractionation?
The splitting of a total radiation dose into many single fractions
Usually 30 lots of 2Gy - 5x a week for 6 weeks
What are the 3 key features of fractionation?
Therefore what does it allow us to do?
- Spares normal tissue by allowing damage repair between doses
- Allows for better recovery of normal tissue than tumour tissue
- Overcomes problem of tumour cell hypoxia
Allows us to give bigger dose without harming healthy tissue
Explain the role of hypoxia in resistance to radiation treatment
Hypoxic tumour cells are resistant to radiation (but occur inevitably due to outgrowth of vascular supply)
Fractionation overcomes this problem - allows reoxygenation of tumour between doses - radiation then targets oxygenated cells
What are the 2 major types of external beam RT?
- Multiple beam RT
- Proton therapy
How does multiple beam radiotherapy work?
Allows superimposing of X-ray dose over tumour region - spares tissue and increases dose to tumour
Usually 4 beams of 0.5Gy each
What is the name of the contraption used to shape the beam to the tumour?
Multileaf Collimator
What are the 3 types of multiple beam RT?
- 3D conformal RT (standard)
- IRMT - more beam angles
- Arc IMRT - 360*
What is the theory behind proton beam therapy?
Why can’t you do this with X-rays?
For protons, Bragg peak (point at which most energy lost) occurs immediately before protons come to rest
Therefore if protons controlled to stop in target tissue, energy will be released here.
X-rays penetrating - cannot be controlled to stop in target tissue - more delivered to healthy tissue.
What is the major risk of radiotherapy?
Carcinogenesis, but actually kills more cells than it damages
What does it mean if tumour growth is exponential?
The more cells there are, the faster they reproduce
Outline the fractional cell kill hypothesis
Chemotherapy kills both tumour cells and bone marrow.
However, bone marrow recovers quicker. By giving chemo at 2 - 3 wk intervals, allows BM to recover a bit, without allowing tumour cells to grow that much
Therefore spares BM with little effect on tumour
Name the 4 classes of chemotherapy considered here
- Alkylating agents
- Topoisomerase inhibitors
- Antimetabolites
- Anti-microtubule agents
What is the mechanism of action of the alkylating agents?
Form cross-links between DNA (inter or intra strand) - cannot replicate - apoptosis
What is the mechanism of action of the topoisomerase inhibitors?
- Topoisomerases break DNA to release tension caused by supercoiling - then repairs itself
- Topoisomerase inhibitors bind to topoisomerase-DNA complex - allows cleavage, but prevents repair
What are antimetabolites?
Give 2 examples
Chemotherapy drugs which resemble nucleoside/nucleotide structure but have altered chemical groups
5 FU, Methotrexate
What is the mechanism of action of methotrexate?
Inhibits dihydrofolate reductase:
Prevents conversion of dihydrofolate to tetrahydrofolate. Therefore no production of purines and hence no DNA synthesis
What is the mehcanism of action of 5FU?
Inhibits thymidylate synthase
What is Capecitabine? Why is it special?
Oral version of 5FU
Prodrug which is activated in the tumour tissue
Give 2 types of antimicrotubule agents
- Vinca alkaloids
- Taxanes
What is the mechanism of action of the vinca alkaloids?
What about Taxanes?
- Vinca alkaloids - prevent spindle formation
- Taxanes - allow spindle formation but prevent depolymerisation so chromosomes stuck in centre of cell
How are PARP1 inhibitors useful in cancer?
PARP1 key for repairing single strand breaks - inhibition leads to further DNA damage - DSB - then repaired - cell survives
In BRCA mutations, cannot repair DSBs - hence by inhibiting PARP1, SSBs become DSBs, which are fatal for the cell
However, no good if no BRCA mutation as DSBs will just be repaired
Give 3 examples of biologically targeted therapies for cancer
- Imatinib
- Herceptin
- Cetuximab
How does Imatinib work/what is it used for?
- Tyrosine kinase inhibitor
- Used in CML - blocks fusion protein which has ++ TK activity
What is the action of Cetuximab?
Blocks EGFR
BUT only works if kras is wild type - otherwise MAPK pathway constitutively active
Define chemoprevention
The use of natural or synthetic compounds to reverse, suppress, prevent or delay carcinogenic progression to invasive cancer
Give some ideal characteristics of chemopreventative agents
Efficacious
Safe
Oral
Low cost
What are the 2 types of chemopreventative agent?
- Cancer-blocking
- Cancer-suppressing
What do cancer-blocking agents do?
Give some examples
Prevent carcinogens from being generated/prevent them reaching/reacting with target
Antioxidants
What do cancer suppressing agents do?
Act after carcinogen exposure to alter gene expression which inhibits cell proliferation/induce apoptosis
What are the 3 stages of chemoprevention
- Primary - healthy people
- Secondary - preneoplastic lesions
- Tertiary - prevention of progression/spread
Give some problems with chemoprevention
- Hard to monitor progress
- Genetic polymorphisms
- Bioavailability
Describe 3 common mechanisms of chemotherapy resistance
- Decreased affinity for receptor
- Inactivation within cell
- Increased efflux via glycoprotein pump
