Biological Basis of Cancer Therapy Flashcards
What are the five most common cancers worldwide?
- Lung
- Breast
- Bowel
- Prostate
- Stomach
What are the four main anti-cancer modalities?
- Radiotherapy
- Chemotherapy
- Surgery
- Immunotherapy
List the different types of cytotoxic chemotherapy
- Alkylating agents
- Pseudoalkylating agents
- Antimetabolites
- Anthracyclines
- Vinca alkaloids and taxanes
- Topoisomerase inhibitors
What are the main types of targeted therapy for cancer?
- Monoclonal antibodies
- Small molecule inhibitors
What is the term used to describe chemotherapy that is given: a. Following surgery b. Before surgery
- Adjuvant
- Neoadjuvant
How do alkylating agents work?
What is a risk in using akylating agents?
1)
- They add an alkyl group to the guanine residues in DNA
- This causes cross-linking of the DNA strands and prevents DNA from uncoiling at replication
- This then triggers apoptosis (via a DNA checkpoint pathway)
- It encourages mis-pairing
2)
- They can result in secondary cancers becuase they cause 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
- So they add platinum to guanine residues which causes DNA cross-linking which prevents the DNA uncoiling during replication - thereby triggering apoptosis via a checkpoint pathway
Name three pseudoalkylating agents
- Carboplatin
- Cisplatin
- Oxaliplatin
What are some side effects of alkylating and pseudoalkylating agents?
- Alopecia (except carboplatin)
- Nephrotoxicity
- Neurotoxicity
- Ototoxicity (platins)
- Nausea, Vomiting,
- Diarrhoea
- Immunosuppression
- Tiredness
How do anti-metabolites work - include 3 types of anti-metabolites?
- They masquerade as purine or pyrimidines leading to inhibition of DNA replication and transcription becuse they incorporate into DNA and cause breakages in the double strands or cause the DNA to be read as errors and cause programmed cell death
- They can also be folate antagonists (dihydrofolate reductase inhibitors)
- This blocks DNA replication and transcription
Give six examples of anti-metabolites
- Methotrexate
- 6-mercaptopurine
- Capecitabine
- Gemcitabine
- 5-fluorouracil
- Fludarabine
State some side effects of anti-metabolites
- Alopecia (not 5-fluorouracil or capecitabine)
- Bone marrow suppression - and associated neutropenia, thrombocytopenia and anaemia
- Increased risk of neutropenic sepsis
- Nausea
- Vomiting
- Mucositis
- Diarrhoea
- Fatigue
- Palmar-plantar erythrodysesthesia (PPE)
How do anthracyclines work?
- 3 ways:
1) They intercalate nucleotides in DNA or RNA sequences - inhibiting transcription and replication
2) Blocks DNA repair - therefore mutagenic
3) Create damaging oxygen free 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 of microtubules
- Taxanes inhibit disassembly of microtubules
- This forces the cells into mitotic arrest
State some side effects of vinca alkaloids / taxanes
- Nerve damage (peripheral neuropathy and autonomic neuropathy)
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression
- Arthralgia (severe joint pain without swelling or signs of arthritis)
- Allergy
How do topoisomerase inhibitors work?
- Topoisomerase is responsible for the unwinding of DNA and they induce temporary single and double strand breaks in the phosphodiester backbone in order to allow DNA replication and transcription
- Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA
- This is unacceptable DNA damage and results in apoptosis at the DNA checkpoint
Give three examples of topoisomerase inhibitors
- Topotecan
- Irinotecan
- Etoposide
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?
SPINAP
- 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?
DIE U
- Dysregulated metabolism
- Inflammation
- Evades the immune system
- Unstable DNA
Give three examples of receptors that are over-expressed in cancer and outline the common reason that overexpression of these receptors may result in cancer
- EGFR – over-expressed in many breast and colorectal cancers
- HER2 – breast
- PDGFR – glioma (brain)
- Over-expression → increased kinase cascade → increased signal amplification
Give an example of a ligand that is over-expressed in some cancers and why might overexpression of certain ligands cause cancer?
- VEGF – prostate, kidney and breast cancer
- It increases the activation of the kinase cascade → increased signal amplification
What do we mean by constitutive receptor activation and give 2 examples in cancer?
- Ligand-independ receptor activation - in this case in regards receptors which lead into the kinase cascades that end in increased cellular proliferation
- EGFR – lung cancer
- FGFR – head and neck cancers, myeloma
What do each of the following suffixes mean in relation to monoclonal antibodies:
1) -momab
2) -ximab
3) -zumab
4) -mumab
1)
–momab Derived from mouse antibodies
2)
–ximab Chimeric antibody
3)
-zumab Humanised antibody
4)
–mumab Fully human antibody
Describe the structure of humanised monoclonal antibodies
- Murine regions are interspersed within 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
- NOTE: they also activate Fc gamma-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 (avastin) – 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 is a popular small molecule inhibitor chemotherapeutic drug?
- 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/cross-talk)
- 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 in BCR-ABL which Glivec targets for example
- Intrinsic resistance
- Intragenic mutations
- Upregulation of downstream signalling pathways
Explain how anti-sense oligonucleotides work
- These are short single-stranded DNA-like molecules
- They hybridise to the complementary sequence on mRNA and hinder its translation
- It then recruits RNase H to cleave the target mRNA Mechanism: anti-sense oligonucleotides
Name a successful B-Raf inhibitor and mention side effects
- 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 inhibitS PD-1
- Nivolumab (anti-PD1 antibody)
Give 2 general resistance mechanisms against general therapeutics against cancer
- DNA repair mechanism upregulation e.g. prevent DNA double stranded breakage → cell survival
- Drugs effluxed from the cell e.g. by ATP-binding cassete (ABC) transporters
Describe the mechanism by which cancer can become resistant to treatment that involves DNA adducts
- DNA adducts may be excised by base excision repair (using PARP)
