L8, Traditional Cancer Therapy Flashcards
What barriers make it difficult to prevent all cancers?
- May prevention strategies rely on personal choice -> non-compliance
- A large percentage of cancers occur at random and are not preventable
List the 3 traditional approaches to cancer therapy, briefly describe each
- Surgery (resection of tumour)
- Radiotherapy (induce cell death by irradiation)
- Chemotherapy (induce cell death using chemical agents)
Surgery: When is it most useful (x2)? Colorectal example. Give a drawback
- Excellent for primary tumours
- Can be used in combined therapy
- Proven 95% 5 year survival in early stage colorectal cancer
- However, not curative if cancer is metastatic
When may surgery be used as a preventative measure?- Stat?
In case of inherited mutations (10-15% of cancers link back to this), tissues may be preemptively removed…
- Familial Adenomatous Polyposis (FAP); large intestine removed
- Breast Cancer Associated (BRCA); mastectomy
- Draining lymph nodes can also be removed
What method might be used to guide surgery?
Fluorescence to aid removal of all of cancerous tissue
e.g. Matrix metalloproteinases which tumours secrete but not healthy cells
Give the 3 types of radiotherapy. Give the 2 characterisations of its application in combined therapy
- External beam therapy
- Brachytherapy
- Systemic
- Neoadjuvant - Before surgery
- Adjuvant -After surgery
Photon Radiotherapy - Outline process, give key sources
- X-ray or gamma rays beamed through; energy decreases as it passes through tissues
- Induces massive DNA damage, particularly in rapidly dividing cells
- Sources include Cobalt and Caesium
Photon Radiotherapy -Mechanisms of action
- Directly ionises DNA; knocks of electron which induces damage
- Inducing free radicals; interacts with water
-> Induction of DNA damage response resulting in either cell cycle arrest and DNA repair or apoptosis
Proton Radiotherapy - overview of mechanism and dose delivery + disadvantage
- Release a localised burst of energy at a focussed point; less damage to healthy cells
- Stays inside tumour rather than passing straight through
- Also causes direct and indirect DNA damage
- Dose primarily delivered at certain point -> Bragg peak
- Technically, sometimes prohibitively difficult
Illustrate the Dose delivery over depth for the to types of external beam radiotherapy
- Initial peak followed by gradual decrease for photon (X-ray)
(Plateau then Bragg peak, then lower plateau for Proton; focussed at tumour site)
Brachytherapy - Outline, Example
- Radioactive material implanted adjacent to tumour cell
- e.g. Uveal Melanoma: Radioactive seeded plaque surgically implanted close to tumour site (I-25, Ru-106)
Describe Systemic Radiotherapy…
Useful isotopes?
What cancers might it be used for?
- Radiopharmaceuticals taken by mouth or injection
- Isotopes used include iodine, strontium, radium
- Can be coupled to a monoclonal antibody to direct drug to tumour
- Used in cancers including thyroid, bone and prostate
Outline the issues associated with radiotherapy resistance
- Tissue specific gene expression; deficient DNA repair mechanisms (e.g. p53, ATM status) -> fail to signal apoptosis
- Hypoxic environment in some solid tumours -> anaemic environment, lack of free radicals induced -> less damage to tumours
How can we improve radiotherapy?
- Increase intratumoral oxygenation using vasoactive agents
- Use more sophisticated treatment deliveries/plans -> inc. 3D conformal radiotherapy, intensity-modulated, stereotactic radiotherapy/surgery
- Use alternative radiation regimens; high energy transfer, new fractionation, combined modality
- High energy proton beam therapy
- Heavy ions such as carbon; still experimental
Chemotherapy and TI
- Most effective against rapidly dividing cells; efficacy depends on amount of drug reaching tumour and residence time
- Non-specific
- Therapeutic index: Difference between minimum effective dose and maximum tolerated dose -> higher TI = fewer side effects
List 5 types of chemotherapies by their targets
- Antimetabolites (interfere with DNA synthesis)
- Anthracyclines (intercalate into DNA)
- Microtubule binders
- Alkylating agents (damage DNA)
- Differentiation (forcing cells to exit cell cycle)
List possible side effects of chemotherapy
Pain, hair loss, trouble breathing, mouth sores, weakened immune system, nausea, vomiting, bruising and bleeding, constipation and diarrhoea, neuropathy, rashes
Antimetabolites; How do they work, what cancers are they used for, give 2 examples…
- Interfere with DNA synthesis, inhibiting nucleic acid synthesis -> S-phase specific
- Require active transport
- Used in breast cancer, leukaemia, lung cancer
- e.g. Methotrexate (MTX), 5-fluorouracil (5-FU)
How does MTX work?
- Analogue of folic acid
- Inhibits dihydrofolate reductase
- Blocks purine and pyrimidine synthesis
Anthracyclines; How do they work, what cancers are they used for, give an example…
- Intercalate into DNA
- S-phase and G2 phases
- Used in breast, bladder, AML
- e.g. Doxorubicin
How does doxorubicin work?
- Inhibits topoisomerase II, preventing replication of DNA
- Prevents relief of torsional stress ahead of replication fork via creation of a nick through which to ‘untangle’
- Seals up these DSBs -> cell death
Microtubule binding agents; How do they work, what cancers are they used for, give examples for the two major classes…
- Produce mitotic arrest, often leading to cell death
- Breast, ovarian, lung
- Microtubule destabilising e,g, Vinka alkaloids
- Microtubule stabilising e.g Taxol
How does Taxol work?
- Block disassembly of mitotic spindle during cell division by stabilising m.tubule polymer
- Prevents chromosomes from achieving metaphase spindle configuration
Alkylating agents; How do they work, give an example…
- Add alkyl groups to guanine bases -> can form intra/interstrand crosslinks
- Work at all parts of the cell cycle but particulalry interfere with DNA replication (S-phase)
- e.g. Cyclophosphamide (bladder and renal toxicity)
Why may dedifferentiating therapies be useful?
- Cancers tend to be de-differentiated -> less specialised, more rapidly proliferating
- Preventing this can make tumour less aggressive
De-differentiation in Acute Promyelotic Leukaemia (APML)
- 95% of cases have reciprocal translocation of Retinoic Acid receptor (RAR) with PML gene
- Fusion protein blocks differentiation
- Myeloid cells revert to ‘Blast’ promyelocyte form
How can APML be treated?
- ATRA (all-trans retinoic acid) + chemotherapy -> ~80% 5 year survival
- May promote proteasomal degradation of RAR-PML fusion protein that blocks differentiation
How may a tumour resist chemotherapy? (list mechanisms)
- Mutation/Loss of receptors e.g. EGFR
- Mutation/Loss of cellular targets
- Decreased uptake (e.g. antimetabolites) or increased efflux
- Inactivation of drugs (e.g. MGMT)
- Increased repair of damage
- Compartmentalisation
- Changes in apoptotic machinery
Combination chemotherapy…
