Biological Basis of Cancer Therapy Flashcards
What are the five most common cancers worldwide? What are the four main anti-cancer modalities?
Lung Breast Bowel Prostate Stomach
Radiotherapy
Chemotherapy
Surgery
Immunotherapy
List the 6 types of cytotoxic chemotherapy.
Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitor
- Apart from vinca alkaloids and taxanes, the rest target rapidly dividing cells targeting their DNA
What are the main types of targeted therapy for cancer?
Monoclonal antibodies
Small molecule inhibitors
Describe the administration and general mode of action
- Given intravenously or by mouth (occasionally) as a monotherapy or in combination
- Works systemically, with curative or palliative intent
- Non “targeted” so affects all rapidly dividing cells in the body
- If given post-operatively = called an adjuvant
- If given pre-operatively = called a neoadjuvant
How do alkylating agents work?
- They add an alkyl group to the guanine residues in DNA
- This causes cross-linking of the DNA strands (intra, inter, DNA-protein) and prevents DNA from uncoiling at replication
- This then triggers apoptosis (via a DNA checkpoint pathway)
- It encourages mis-pairing
Name four alkylating agents.
Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide
How do pseudoalkylating agents work?
They have the same mechanism as alkylating agents but use platinum instead of alkyl groups
Name three pseudoalkylating agents.
Carboplatin
Cisplatin
Oxaliplatin
What are some side effects of alkylating and pseudoalkylating agents?
Nephrotoxicity Alopecia (except carboplatin) Neurotoxicity Ototoxicity (platins) Nausea, Vomiting, Diarrhoea, Immunosuppression, Tiredness
How do anti-metabolites work?
- They masquerade as purine or pyrimidines
- They can also be folate antagonists, folic acid being an important building block for all nucleic acids (dihydrofolate reductase inhibitors)
=> This leads to inhibition of DNA replication and transcription
Give six examples of anti-metabolites.
Methotrexate (folate) Capecitabine Gemcitabine (pyrimidine) Fludarabine (purine) 5-fluorouracil 6-mercaptopurine
State some side effects of anti-metabolites.
- Alopecia (not 5-fluorouracil or capecitabine)
- Bone marrow suppression, anaemia, neutropenia and thrombocytopenia
- Increased risk of neutropenic sepsis
- Nausea, Vomiting, Fatigue
- Mucositis and Diarrhoea
- Palmar-plantar erythrodysesthesia (PPE)
How do anthracyclines work?
- Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand.
- Block DNA repair - mutagenic
- They create DNA and cell membrane damaging free oxygen radicals
Give two examples of anthracyclines.
Doxorubicin
Epirubicin
State some side effects of anthracyclines.
- Cardiac toxicity (probably due to the free radicals)
- Alopecia
- Neutropenia
- Nausea, Vomiting, Fatigue
- Red urine (doxorubicin – ‘the red devil’)
How do vinca alkaloids and taxanes work?
Vinca alkaloids inhibit assembly and taxanes inhibit disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest
List the side effects of microtubule targeting drugs (vinca alkaloids and taxanes)
- Peripheral neuropathy, autonomic neuropathy
- Alopecia
- Nausea, Vomiting
- Bone marrow suppression (neutropenia, anaemia etc)
- Arthralgia
- Allergy
Why is topoisomerase important? Hence, explaining how topoisomerase inhibitors work?
- Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription
- They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA
- They protect the free ends of DNA from aberrant recombination events
=> Topoisomerase inhibitors alter binding to DNA and allow permanent DNA breaks.
Give three examples of topoisomerase inhibitors.
Topotecan (topo1)
Irinotecan (topo1)
Etoposide (topo2)
State some side effects of topoisomerase inhibitors.
Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis; so they are given atropine)
- Hair loss
- Nausea, Vomiting, Fatigue
- Bone marrow suppression
What are the six hallmarks of cancer?
- Self-sufficient
- Pro-invasive and metastatic
- Insensitive to anti-growth signals
- Non-senescent
- Anti-apoptotic
- Pro-angiogenic
What are the four hallmarks of cancer that have recently been added?
Dysregulated metabolism
Inflammation promoting
Evades the immune system
Unstable DNA
Give three examples of receptors that are over-expressed in cancer. State the cancer types
EGFR – over-expressed in many breast and colorectal cancers
HER2 – breast
PDGFR – glioma (brain)
=> increased kinase cascade and signal amplification
Give an example of a ligand that is over-expressed in some cancers.
Vascular Endothelial growth factor (VEGF) – prostate, kidney and breast cancer
Give two examples of constitutive (ligand independent) receptor activation in cancer.
EGFR – lung cancer
FGFR – head and neck cancers, myeloma
What do each of the following suffixes mean in relation to monoclonal antibodies:
a. -momab
b. -ximab
c. -zumab
d. -mumab
momab = Derived from mouse antibodies ximab = Chimeric antibody zumab = Humanised antibody mumab = Fully human antibody
Describe the structure of humanised monoclonal antibodies.
Murine regions are interspersed within the with the light and heavy chains of the Fab portion
Describe the structure of chimeric monoclonal antibodies.
The murine component of the variable region of the Fab section is maintained integrally
What effect can monoclonal antibodies have on receptors and their activation?
- They target the extracellular component of receptors and can prevent receptor dimerization, neutralise the ligand and cause internalisation of the receptor
- They also activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC)
Give two examples of monoclonal antibodies used in oncology.
Bevacizumab – binds and neutralises VEGF
Cetuximab – targets EGFR
How do small molecule inhibitors work?
They bind to the kinase domain of tyrosine kinase receptors within the cytoplasm and block autophosphorylation and downstream signalling
What was the first targeted treatment for cancer and how did it work?
Glivec (imatinib) – it is a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1
This inhibits the kinase activity of ABL1
Give four examples of small molecule inhibitors that inhibit receptors.
Erlotinib (EGFR)
Gefitinib (EGFR)
Lapatinib (EGFR/HER2)
Sorafenib (VEGFR)
Give three examples of small molecule inhibitors that inhibit intracellular kinases.
- Sorafenib (Raf kinase) – this is in addition to its anti-VEGFR effects
- Dasatinib (Src kinase)
- Torcinibs (mTOR inhibitors)
State some advantages and disadvantages of monoclonal antibodies.
Advantages:
- High target specificity
- Cause ADCC, complement-mediated cytotoxicity and apoptosis induction
- Can be radiolabelled
- Long half-life
- Good for haematological malignancies
Disadvantages:
- Large and complex structure
- Less useful against bulky tumours
- Only useful against targets with extracellular domains
- Not useful for constitutively activated tumours
- Cause immunogenicity and allergy
- IV administration
- Expensive
State some advantages and disadvantages of small molecule inhibitors.
Advantages:
- Can target tyrosine kinases without an extracellular domain or which are constitutively activated
- Pleiotropic targets (useful in heterogenic tumours)
- Oral administration
- Good tissue penetration
- Cheap
Disadvantages:
- Shorter half-life, more frequent administration
- Pleiotropic targets (more unexpected toxicity)
State some resistance mechanisms to targeted therapies.
- Mutations in ATP binding domain
- Intrinsic resistance
- Intragenic mutations
- Upregulation of downstream signalling pathways
Explain how anti-sense oligonucleotides work.
These are short single-stranded DNA-like molecules
They bind to the complementary sequence on mRNA and hinder its translation
It then recruits RNase H to cleave the target mRNA
Name a successful B-Raf inhibitor.
Vemurafenib
NOTE: side effects include arthralgia, skin rash and photosensitivity
Explain how the PD-1 receptor-PDL1 ligand system works.
PD-1 receptor is on the cell membrane
When the ligand (PDL-1) binds to the PD-1 receptor, the body’s T cells can no longer recognise tumours as foreign
So blocking the PD-1 receptor will stimulate the immune system
Name a drug that inhibiting PD-1.
Nivolumab (anti-PD1 antibody)
