Resistance to chemotherapy Flashcards
Primary chemotherapy resistance
- Decreased drug activity, regardless of drug exposure.
- Also referred to as ‘intrinsic resistance’.
Acquired chemotherapy resistance
- Resistance develops during or after the course of treatment.
- Drug-resistant cancer cells with secondary genetic modifications acquired during the course of therapy.
Development of acquired resistance
- Dividing cancer cells acquire mutations at a high rate.
- Cells in a tumour, while similar, are NOT genetically identical
- When exposed to a cancer drug, the sensitive cells are killed, but this will not affect the whole mass of the tumour.
- Resistant cells survive and multiply.
Combatting acquired resistance
- Combination of chemotherapy drugs with different mechanisms of action.
- Tumour is unlikely to be resistant to several drugs.
Mechanisms of metastases resistance
- Efficient repair to damaged DNA
- Decreased intracellular activation
- Increased intracellular breakdown
- Bypass biochemical pathways
- Overproduction of blocked enzyme
- Changes to receptor
What is a cellular mechanism of defence, of a cancer cell, to alkylating agents?
Efficient repair to damaged DNA
What is a cellular mechanism of defence, of a cancer cell, to methotrexate?
- Decreased uptake by cell
- Bypass biochemical pathways
- Gene amplification/ overproduction of blocked enzyme
What is a cellular mechanism of defence, of a cancer cell, to doxorubicin?
Decreased uptake by cell
What is a cellular mechanism of defence, of a cancer cell, to vinca alkaloids?
Increased drug efflux
What is a cellular mechanism of defence, of a cancer cell, to anthracyclines?
Increased drug efflux
What is a cellular mechanism of defence, of a cancer cell, to 5-fluorouracil?
Decreased intracellular activation
What is a cellular mechanism of defence, of a cancer cell, to cytarabine?
Increased intracellular breakdown
Oncogene
- Gene that gains function when mutated
- Example = EGFR
- Mutated EGFR = promotion of angiogenesis
Tumour suppressor gene
- Gene that loses function when mutated
- Example = P53
- Mutated P53 = suppresses apoptosis therefore promotes cancerous cell growth
Multidrug resistance
Simultaneous resistance to many structurally and functionally unrelated drugs
Causes of multidrug resistance
- Abundance of ATP-dependent efflux pumps with broad specificity.
- Upregulation of ‘MDR1’ gene
- Other pathways that lead to defective apoptopic pathways
- Other pathways that lead to reduced drug uptake
ATP-dependent efflux pumps
Increased efflux = reduced intracellular concentration
Upregulation of MDR1 gene
- Codes for p-glycoprotein (PGP)
- PGP increases drug efflux
Deisgning a chemotherapy regimen
- Avoid drugs with similar MoA
- Choose drugs with complimentary MoA
- e.g. FEC
FEC
- Fluorouracil – inhibits thymidylate synthase, preventing DNA synthesis
- Epirubicin – forms a complex with DNA by intercalating between base pairs
- Cyclophosphamide – forms DNA and RNA cross-links (not cell cycle specific)
Methotrexate (folate antagonist)
- Inhibits dihydrofolate reductase (DHFR) - essential enzyme in folate metabolism.
- Folate is an enzyme that maintains levels of tetrahydrofolate FH4.
- Without tetrahydrofolate FH4, synthesis of DNA building blocks (dTMP) is inhibited.
- Decreases DNA synthesis, repair and cell division.
Methotrexate - resistance mechanism
- Overexpression of DHFR
- Uncontrolled proliferation of cancer cells
Cisplatin (alkylating agent)
- Forms crosslinks with purine bases on DNA
- Interferes with DNA repair mechanisms
- Leads to DNA damage and induces apoptosis
- Uptake influence by copper transporter 1 (CTR1)
Cisplatin - resistance mechanism
- Mutation or deletion of gene coding for CTR1 = resistance
- Reduced expression of CTR1 = less uptake of cisplatin
- Sulphur-containing molecules can bind with cisplatin and promote efflux
Herceptin (trastuzumab) - resistance mechanism
- HER2 (human epidermal growth factor 2) inhibitor
- Truncated receptors prevent antibody binding
- Upregulation of signal transduction pathways
Lapatinib
- Developed for HER2+ BrCa resistant to trastuzumab.
- Active against HER1 and HER2
- Tyrosine kinase inhibitor
- Small molecule - can cross cell membrane.
- Effective even if truncated HER2 receptor.
Cell kill hypothesis
- Cancer cells ‘recover’ between cycles
- Delays in treatment = further increase in number of cells.
- Can lead to resistance as:
- Partial exposure to chemotherapy – potential
for mutation to overcome mechanism of action - Cells multiply, resistance conferred to new cells
- Tumour becomes populated with resistant cells
- Partial exposure to chemotherapy – potential
