Biological basis of cancer therapy Flashcards
What are the main chemotherapeutic approaches to treating cancer?
Cytotoxic chemotherapy: Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
What are the main targeted approaches to treating cancer?
Small molecule inhibitors
Monoclonal antibodies
Why do many cancer treatments cause side effects?
They act systemically - don’t differentiate between cancerous cells and normal cells
Cytotoxics target ALL rapidly dividing cells –> hair and intestinal epithelium
How can side effects of cancer treatments be minimised?
Alopecia - scalp cooling Neutropaenia, anaemia, thrombocytopaenia - transfusions/platelets/GCSF/dose reduction Nausea and vomiting - anti-emetics PPE - pyridoxine (vit B6) Mucositis - mouth washes Diarrhoea - loperamide Cardiac toxicity - cap dosing
What is the rationale behind developing new targets and new drugs in cancer treatment?
There’s a big problem with RESISTANCE to cytotoxic and targeted therapies
How do anthracyclines work?
- Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within DNA/RNA strand
- Block DNA repair (mutagenic)
- Create DNA and CM damaging oxygen free radicals
How do vinca alkaloids and taxanes work?
Inhibit assembly (vinca alkaloids) or disassembly (taxanes) of MITOTIC MICROTUBULES causing dividing cells to undergo mitotic arrest
How do topoisomerase inhibitors work?
Topoisomerases are responsible for uncoiling of DNA - prevent DNA torsional strain during DNA replication and transcription
- Induce temporary single strand (topo1) or double strand (topo2) breaks in phosphodiester backbone of DNA
- Protect free ends of DNA from aberrant recombination events
- Some alter binding of complex to DNA and allow permanent DNA breaks
How do monoclonal antibodies work?
- Target extracellular component of receptor tyrosine kinases, e.g. EGFR over-expressed in breast, colorectal cancer
- Neutralise ligand
- Prevent receptor dimerisation
- Cause internalisation of receptor
Activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytoxictiy (ADCC)
How do small molecule inhibitors work?
- Bind to receptor protein tyrosine kinases and intracellular kinases
- Block autophosphorylation and downstream signalling
- Block cancer hallmarks, e.g. VEGF inhibitors inhibit angiogenesis
How do cytotoxics work in general?
“Select” rapidly dividing cells by targeting their structures (mostly DNA)
Work systemically
Non-targeted - affects all rapidly dividing cells in body, e.g. hair and intestinal epithelium
When can cytotoxic chemotherapy be used?
Post-operatively = adjuvant - to mop up any loose cells and improve prognosis
Pre-operatively = neoadjuvant - attempt to downstage tumour if tumour is too large + inoperable
As a monotherapy or in combination
With curative or palliative intent - improve symptoms and disease burden
What are the advantages of monoclonal antibodies?
- High target specificity
- Cause ADCC, complement mediated cytotoxicity and apoptosis induction
- Can be radiolabelled
- Cause target receptor internalisation
- Long half-life tf lower dosing frequency
- Good for haematological malignancies
- Liked by regulatory authorities
What are the disadvantages of monoclonal antibodies?
- Large and complex structure (low tumour or BBB penetrance)
- Less useful against bulky tumours
- Only useful against targets with extracellular domains
- Not useful for constitutively activated receptors
- Cause immunogenicity, allergy
- Parenteral (IV) admin
- Risky
- Expensive
What are the disadvantages of small molecule inhibitors?
- Shorter half-life, more frequent admin
- Pleiotropic targets (more unexpected toxicity)
