Biological Basis of Cancer Therapy Flashcards
What are the five most common cancers worldwide?
Lung Breast Bowel Prostate Stomach
most common for men is lung, women is breast
What are the four main anti-cancer modalities?
Radiotherapy
Chemotherapy
Surgery
Immunotherapy
List the different types of cytotoxic chemotherapy, how they can be taken and what cells they act on.
Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
- target ALL rapidly dividing cells
- given orally or IV function systematically
What are the main types of targeted therapy for cancer?
Monoclonal antibodies
Small molecule inhibitors
hat is the term used to describe chemotherapy that is given:
a. Following surgery
b. Before surgery
Adjuvant- post operatively
Neoadjuvant- pre operatively
How do alkylating agents work?
- add an alkyl group (CnH2n+1) 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 (oncogenic)
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?
Alopecia (except carboplatin) Nephrotoxicity Neurotoxicity Ototoxicity (platins) Nausea, Vomiting, Diarrhoea, Immunosuppression, Tiredness
How do anti-metabolites work?
- masquerade (are analogues) of purine or pyrimidines
- leads to inhibition of DNA replication and transcription - they can also be folate antagonists (dihydrofolate reductase inhibitors) needed to make folic acid needed to make nucleic acids
Give six examples of anti-metabolites.
Methotrexate - Folate
6-mercaptopurine, decarbazine and fludarabine (purine)
5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
State some side effects of anti-metabolites.
Alopecia (not 5-fluorouracil or capecitabine)
Bone marrow suppression
Increased risk of neutropenic sepsis
Nausea, Vomiting, Mucositis, Diarrhoea, Fatigue
Palmar-plantar erythrodysesthesia (PPE)
How do anthracyclines work?
- They intercalate into DNA or RNA sequences and inhibit transcription and replication
- It also blocks DNA repair
- They create DNA damaging and cell membrane 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 mitotic microtubules
Taxanes inhibit disassembly of mitotic microtubules
This forces the cells into mitotic arrest
State some side effects of these drugs.
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
Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA
Give three examples of topoisomerase inhibitors.
Topotecan
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?
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.
EGFR – over-expressed in many breast and colorectal cancers
HER2 – breast
PDGFR – glioma (brain)
Give an example of a ligand that is over-expressed in some cancers.
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
a.–momab Derived from mouse antibodies b.–ximab Chimeric antibody c.–zumab Humanised antibody d.–mumab Fully human antibody
murine- refers to from a mouse
Fab= region on antibody that binds to antigen
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
NOTE: 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 (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 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/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
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
Mechanism: anti-sense oligonucleotides
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) used in melanoma, non-small lung cancer and renal cell carcinoma
What types of genetic mutation cause cancer?
- Chromosome translocation
- Gene amplification
- Point mutations (in promoter/enhancer regions)
- Deletions/Insertions
- Epigenetic alterations
- Heritable mutations
What is systemic therapy and what two categories is it split into?
cancer treatment that targets the entire body
- cytotoxic chemotherapy
- targeted therapies
What is the significant of the b-Raf mutation in cancer?
60% of melanomas had this mutation
- substitution of glutamic acid to valine caused 5000x increase in activity
What is PD-1 and what is it’s relevance in cancer?
PD-1 (Programmed cell death protein 1) is present on surface on cancer cells and is required to maintain T-cell activation
After binding it w the ligand PDL-1 body can no longer recognise tumour cells as foreign.
If either is blocked, immune system is stimulated
What’s the unit of 1 gray?
absorption of 1 joule of radiation energy per kilogram of matter
