Biological Basis of Cancer Therapy Flashcards
How is the incidence of cancer set to change in the future?
Incidence set to increase with a reduction in infection-based cancers and an increase in western cancers due to greater westernisation in developing countries
What are the four main modalities of anti-cancer therapy?
Surgery
Chemotherapy
Radiotherapy
Immunotherapy
What are the six types of genetic mutations that can cause cancer?
Chromosome Translocation
Gene Amplification (Copy Number Variation)
Point Mutations within promoter or enhancer regions of the genes
Deletions or insertions
Epigenetic alterations to gene expression
Can be inherited
What are the five main types of Cytotoxic Chemotherapy?
Alkylating agents
Antimetabolites
Anthracyclines
Vinca alkaloids and taxanes
Topoisomerase inhibitors
What is the principle of action behind Cytotoxic chemotherapy?
The drugs ‘select’ rapidly dividing cells by targeting their structures (mostly DNA)
(Non-targeted - they affect all rapidly dividing cells e.g. hair and intestinal epithelium)
What are the three different times at which Chemotherapy can be used?
Post-operatively - Adjuvant
Pre-operatively - Neoadjuvant
As a monotherapy or in combination
(with Curative or Palliative intent)
How do Alkylating agent work?
They add Alkyl groups to guanine residues in DNA
This cross-links DNA strands and prevents DNA from uncoiling at replication
This triggers apoptosis (via DNA checkpoint pathway)
It encourages mispairing
How do Pseudo-alkylating agents work?
These add platinum to guanine residues in DNA
Same mechanism of death as alkylating agents
(This cross-links DNA strands and prevents DNA from uncoiling at replication. This triggers apoptosis)
Name 4 Alkylating agents:
Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide
Name three Pseudo-alkylating agents:
Carboplatin
Cisplatin
Oxaliplatin
Name 9 common side effects of Alkylating and Pseudo-Alkylating agents:
Hair loss (not carboplatin)
Nephrotoxicity
Neurotoxicity
Ototoxicity (platins) (ear)
Nausea
Vomiting
Diarrhoea
Immunosuppression
Tiredness
How do anti-metabolites work?
They masquerade as purine or pyrimidine residues
They lead to the inhibition of DNA synthesis, breaking of the double-strand and apoptosis
They block DNA replication and DNA transcription
What are the three main types of Anti-metabolites?
Purine Analogues
Pyrimidine Analogues
Folate Antagonists
What do folate antagonists do?
What type of chemotherapeutic are they?
Anti-metabolites
They inhibit dihydrofolate reductase which is required to make folic acid - an important building block for all nucleic acids (especially thymine)
Give 6 examples of anti-metabolites:
Methotrexate (Folate antagonist)
6-mercaptopurine
Fludarabine (purine)
5-fluorouracil
Capecitabine
Gemcitabine (pyrimidine)
What are common side effects of anti-metabolites?
Hair loss (not 5-flourouracil or capecitabine)
Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
Increased risk of neutropenic sepsis or bleeding
Nausea and vomiting
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia
Fatigue
How do Anthracyclines work?
(3 ways)
Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand
They also block DNA repair (mutagenic)
They create DNA-damaging and cell membrane damaging oxygen free radicals
Give two examples of anthracyclines:
Doxorubicin
Epirubicin
Give eight common side effects of anthracyclines:
Cardiac toxicity (Arrhythmias, heart failure) (Probably due to damage by free radicals)
Alopecia
Neutropenia
Nausea
Vomiting
Fatigue
Skin changes
Red Urine
How do Vinca Alkaloids and Taxanes work?
They inhibit the assembly (Vinca alkaloids) or disassembly (taxanes) of Mitotic microtubules causing dividing cells to undergo mitotic arrest
What are common side effects of Vinca Alkaloids and Taxanes?
Nerve damage: peripheral neuropathy, autonomic neuropathy
Hair loss
Nausea
Vomiting
Bone marrow suppression (neutropenia, anaemia etc.)
Arthralgia (severe pain in a joint without swelling or other signs of arthritis)
Allergy
How do Topoisomerases work?
Topoisomerases are responsible for the uncoiling of DNA
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
How do Topoisomerase Inhibitors work?
Specific Topoisomerase inhibitors alter the binding of the complex to DNA and allow permanent DNA breaks
Drugs, such as anthracyclines, have anti-topoisomerase effects through their action on DNA
Give some examples of Topoisomerase Inhibitors:
Topotecan (topo 1)
Irinotecan (topo 1)
Etoposide (topo 2)
What are the common side effects of Topoisomerase inhibitors?
What does this mean they are frequently coadministered with?
Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis (sweating) - they are therefore given atropine)
Hair loss
Nausea
Vomiting
Fatigue
Bone marrow suppression
What are the three common Resistance mechanisms to chemothrapy?
DNA repair mechanisms upregulated and DNA damage is repaired
DNA adducts replaced by Base Excision repair
Drug effluxed from cell by ATP-binding cassette transporters
How has supportive care for chemotherapeutics been improved?
GCSF (Granulocyte-colony stimulating factor)
Bone marrow transplants
Anti-emetics
All reduce impact of side-effects
How do Small Molecule Inhibitors and Monoclonal antibodies tend to work, and what is the problem with them?
How are we combatting this?
Tend to ‘cut’ cell signals which can be effective in monogenic cancers but in more complex cancers parallel pathways and feedback cascades are activated
We have started to use Dual Kinase Inhibitors which prevent feedback loops but increase toxicities
What is the Acronym for the six hallmarks of cancer?
What does it stand for?
SPINAP
Self-sufficient
Pro-invasive and metastatic
Insensitive to anti-growth signals
Non-senescent
Anti-apoptotic
Pro-angiogenic
What are the four new, additional hallmarks of cancer?
What is their acronym?
DIE U
Dysregulated metabolism
Inflammation
Evades the immune system
Unstable DNA
What are three causes of the rapid growth of cancer cells?
Over-expression of Growth Factor receptors
e.g. HER2, EGFR
Over-expression of Ligand
e.g. VEGF
Constitutive Receptor activation
e.g. EGFR, FGFR
Which all lead to downstream kinase cascade amplification
Where are -zumab Monoclonal antibodies derived from?
Example?
Humanised
e.g. Bevacizumab
Where are -momab Monoclonal antibodies derived from?
Derrived from mouse antibodies
Where are -mumab Monoclonal antibodies derived from?
Example?
Fully Human
e.g. Panitumumab
Where are -ximab Monoclonal antibodies derived from?
Example?
Chimeric
e.g. Cetuximab
How do Monoclonal antibodies work?
Bind to Extracellular component of the growth factor receptor and:
Neutralise the ligand
Prevent receptor dimerisation
Cause internalisation of the receptor
Activate Fcγ-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)
How does Bevacizumab work?
Binds and neutralises VEGF
- shown to increase survival in colorectal cancer
How does Cetuximab work?
Targets EGFR
How do Small Molecule Inhibitors work?
Bind to the kinase domain (inside cell) on the growth factor receptor and block autophosphorylation and downstream signalling
What is Glivec and how does it work?
First targeted therapy:
‘73 a Chromosome translocation in patients with chronic myeloid Leukemia was discovered that created a unique fusion protein called Bcr-abl - enzyme which drove over-production of white cells
Glivec targets ATP binding region within Kinase domain which inhibits the activity of ABL1
Apart from receptor protein tyrosine kinases, where else can small molecule inhibitors work?
Intracellular kinases - therefore they can affect cell signalling pathways to block cancer hallmarks without the toxicity of cytotoxics
What is the main problem with Targeted Therapies?
Resistance
What are the four main resistance mechanisms in Targeted therapies?
- Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
- Intrinsic resistance (Herceptin is effective in 85% of HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream of parallel pathways (that lead to cell proliferation)
How do Anti-sense Oligonucleotides work as a targeted therapy?
Single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
This complementary nucleic acid hybridisation to the target gene hinders translation of specific mRNA
It recruits RNase H to cleave target mRNA
This is good for ‘undruggable’ targets
What is the major obstacle to Targeted Therapy of cancer?
Tumour Heterogeneity
