Lecture 8 Flashcards
Why is cancer still prevalent
- Many prevention strategies rely on personal choices
- Large percentage of cancers occur randomly and aren’t preventable
Traditional cancer therapies
Surgery - Resection of tumour
Radiotherapy - induce cell death by irradiation
Chemotherapy - Induce cell death using chemical agents
Surgical oncology
- Good for primary tumours and often used alongside other therapies
Examples:
- Early stage colorectal cancer - surgery alone can create a 95% survival rate after 5 years
- Can be preventative for cancer predisposition syndromes:
Familial adenomatous polyposis - Large intestine removal
Breast cancer associated - mastectomy - Draining lymph nodes can be removed
- Some metastases can be removed via surgery but often impractical
Fluorescence guided surgery
Aim: Remove cancerous tissue and small healthy margin
Challenge: How does surgeon know where cancer is?
Answer: Fluorescence guided surgery
Radiotherapy
- Often used with surgery/other therapies
- Used before (neoadjuvant) and after surgery (adjuvant)
- Damages normal cells
- Cancer cells often more sensitive as more rapid division and mutated DNA pathways
Main types of radiotherapy and issues
- External beam therapy (outside body source)
- Brachytherapy (material adjacent to tumour)
- Systemic (liquid by mouth or IV)
Issue is tumour suppressor mutation could cause resistance
External beam therapy
- Uses X-ray or gamma rays (both photon therapy)
- Proton beam therapy
Photon therapy:
- Small packets of high energy light
- Photon energy decreases as it goes through the body
- Healthy cells damaged
- Continues travelling after hitting the tumour
Proton therapy:
- Small subatomic particles
- Super-charged protons release burst of energy when they stop
- Fewer healthy cells damaged
- Stay inside the tumour
Photon therapy mechanism
- Directly ionises DNA
- Induces free radicals, including ROS, indirectly damaging DNA
- Induction of DNA damage leads to cell cycle arrest/DNA repair OR apoptosis
Proton-beam therapy
Causes direct/indirect DNA damage
Hydrogen atom has electron removed, accelerating the remaining proton energy
What cancers can proton-beam therapy treat?
- Up until recently, was only able to treat a limited number of cancer e.g. Uveal melanoma
- New proton beam centres in Manchester and London
- Appropriate for treating paediatric cancers, keep damage to surrounding tissue at a minimum
Brachytherapy
Brachytherapy uses iodine-125 (more preferred in the US) or Ruthenium-106 (more preferred in Europe) to treat Uveal melanoma
Second double dose of Brachytherapy has shown to decrease the need for enucleation as tumour size decreases
Systemic therapy
- Radiopharmaceuticals - liquid drug taken by mouth or injection
- Radioactive isotope e.g. iodine, strontium, samarium or radium
- Coupled to a monoclonal antibody to direct drug to tumour
Cancer examples: thyroid, bone, and prostate cancers
Radiotherapy resistance
Cancer mutations: p53 mutations: DNA damage is less likely to induce apoptosis
Solid tumours are often in hypoxic environments, so less production of ROSs.
How can we improve radiation therapy?
- Increase intertumoral oxygenation - Use vasoactive agents to increase blood flow
- Sophisticated treatment planning and delivery:
3D conformal radiotherapy
Intensity modulated radiotherapy
Stereotaxic radiotherapy/radiosurgery - Alternative radiation regimens:
High energy transfer regimens
New fractionation regimens
Combined-modality regimens
Alternative radiation types:
- High energy proton beam therapy
- Heavy ions e.g. carbon
Chemotherapies
Agents disrupt proliferation
Effective against rapidly dividing cells
Efficacy depends on drug reaching tumour and residence time
Non specific, so side effects
Therapeutic index (TI)_
- Difference between minimum effective dose and maximum tolerated dose
- The higher the TI, the fewer side effects there are
What are the 4 kinds of chemotherapy
Neoadjuvant chemotherapy - Shrink tumour before surgery/radiation to improve chances that surgery/radiation will be effective
Adjuvant chemotherapy - Post surgery to kill any remaining cells
Curative chemotherapy - Single chemotherapy to cure cancer e.g. lymphoma or leukaemia
Palliative chemotherapy - For patients with advanced/metastatic cancer to help delay cancer growth and manage symptoms
Traditional chemotherapy on the cell cycle
- Antimetabolites - interfere with DNA synthesis in S-phase
- Anthracyclines - Intercalate into DNA: S/G2
- Alkylating agents: Damage DNA in all phases except S
- Microtubule binders - inhibit M-phase
- Differentiation - force cells to exit cell cycle in G0
Name some of the most common side effects of chemotherapy
Hair loss
Mouth sores
Weak immune system
Bruising
Nausea/vomiting
Anti-metabolites
Interfere with DNA synthesis in S-phase by inhibiting nucleic acid synthesis
Require active transport
Used in treating breast and lung cancers, leukaemia
Include:
- Methotrexate - Analogue of folic acid that inhibits dihydrofolate reductase - blocks nucleic acid synthesis and DNA synthesis
- 5-fluorouracil
Anthracyclines
Doxorubicin intercalates into DNA and inhibits topoisomerase II preventing relaxation of DNA supercoils
Leads to a build up of cytotoxic DNA double strand breaks, including cell death
Used to treat bladder, breast cancers, and acute lymphocytic leukaemia
Alkylating agents
- Add alkyl groups to nucleotide bases
- Can lead to interstand and intrastand cross-links
- Multiple side effects
Cyclophosphamide typically used:
- Cross-links guanines
- Bladder and renal toxicity
Microtubule binding agents
- Structurally complex organic bases
- Natural/Semi-synthetic
Classes:
- Microtubule destabilising drugs e.g. Vinka alkaloids
- Microtubule stabilising drugs e.g. taxol
Cause mitotic arrest and cell death
Taxol
- Produced by fungus derived from pacific yew tree
- Blocks disassembly of mitotic spindle by stabilising microtubule polymer
- Chromosomes unable to achieve metaphase spindle
- Treats late-stage, breast, ovarian and lung cancers
