Drug Resistance Flashcards
What is drug resistance in cancer patients
(What are the 2 types)
○ Patients often had an excellent initial response but on relapse did not respond to chemotherapy - Acquired Drug Resistance
○ Some tumours did not respond to chemotherapy from the outset - Intrinsic Drug Resistance
○ Thus the clinical evidence for drug resistance appeared at the dawn of chemotherapy
What are the factors of drug resistance found in humans
Low serum levels (poor absorption, rapid metabolism/excretion)
Dose reduction (due to toxicity, especially in elderly)
Drug delivery (High molecular weight compounds, bulky tumour)
Tumour-host interaction (local metabolism of drug, tumour blood supply)
Explain how microenviroments affects cancer drugs delivery especially concerning tumour blood supply
○ Many anticancer drugs have poor distribution from blood vessels in solid tumours: irregular vasculature and high interstitial pressure limiting drug penetration
○ Also, the composition of the extracellular matrix, cell–cell adhesion, drug metabolism and binding contribute to limited drug distribution.
○ Hypoxia induces a more aggressive phenotype
How do drug resistance in tumours arise
○ Tumours are heterogeneous and become more heterogeneous as they progress
○ They are genetically unstable. Cytogenic plasticity (aneuploidy, polyploidy, rearrangements) is a characteristic of tumour cells
○ They can rapidly alter gene expression
○ Subpopulations may be more resistant to chemotherapy than others
(Cancer is micro-evolution and natural selection at its worst)
Explain how tumour heterogeneity leads to a drug resistance tumour
- Single founder cell acquires mutations and generate subclones.
- Some new mutations lead to accelerated growth and expansion
- Others (less fit) die out
- Drug treatment leads to selective survival of a drug resistant clone
- Heterogeneity is re-established rapidly through acquisition of mutations by daughter cells of the resistant clone
What is the best approach drug resistant tumours formed from heterogeneity
- Cocktails of drugs with non-overlapping mechanisms of action and resistance are more likely to kill a higher proportion of cancer cells for lasting benefit.
Resistance mechanisms in tumours derive from _
normal cell protective and survival mechanisms
Narrow therapeutic window
What are the cellular mechanism in drug resistance in cancer patient
- Accumulation: Uptake, efflux, sequestration, nuclear transport
- Metabolic: Decreased activation, increased de-activation. Upregulation of alternative pathways
- Target alteration: Increased/ decreased target, mutation that decreases affinity for drug
- Adaptive responses: Increased DNA repair, development of tolerance
- Survival Signalling and inhibition of cell death : Increased survival signalling, Decreased cell death signalling
- Stem cells: Possess all of the above
How does reduced accumulation work in treatment resistance tumours
Reduced uptake
Mostly applies to mimics of natural substrates. Some drugs enter the cell rapidly via membrane transporters
Downregulation of uptake reduces intracellular concentration
e.g. antifolates like methotrexate
(Enters via the reduced folate carrier. Downregulation of RFC confers resistance.)
Explain the clinical observation seen in drug efflux (multi-drug resistance)
- Resistance to several drugs that are structurally diverse and have different cellular targets. (These drugs are often lipophilic natural products or synthetic derivatives)
- Cancer cells selected for resistance to one drug are often cross-resistant to other drugs: Multi-drug resistant (MDR)
- Cells with MDR phenotype over-express plasma membrane drug efflux pumps, called ABC transporters
[First to be identified was Pgp (MDR1)]
Clinical evidence links expression of these pumps to intrinsic and acquired resistance to anticancer drugs.
How is increased activation of metabolism in drug resistant tumours
Example -
- Some drugs require intracellular activation to the active metabolite
- Natural folates are retained within the cell by polyglutamation by folylpolyglutamate synthase (FPGS)
- This also increases their affinity for the enzymes that use them
Glutamate residues are removed by y-glutamyl hydrolase (y-GH) - FPGS and y-GH also act on antifolates
- Resistance can be due to decreased FPGS and increased y-GH
How does upregulation of targets occur in drug resistant tumours
For drugs that are competitive inhibitors of natural substrate, resistance may develop by upregulation of target enzyme
(Resistance to antifolates e.g. Methotrexate (inhibits DHFR), raltitrexed (inhibits TS) often due to upregulation of DHFR or TS)
There can also be increase de-activation in metabolism in drug resistant tumours
Examples -
Glutathione (GSH) is the most abundant cellular non-protein thiol.
It is a hydrogen donor and intercepts electrophilic drug intermediates that would otherwise attack DNA, RNA and proteins
Glutathione S-transferases (GSTs) use GSH to inactivate potentially harmful spp. by conjugation.
Drug conjugates are then exported and readily removed from the body
How does downregulation of targets occur in drug resistant tumours
Sensitivity to some drugs correlates with activity of target enzyme e.g. the topoisomerase poisons
Topoisomerase poisons trap the enzyme on the broken DNA and prevent rejoining
Cytotoxicity is directly related to topoisomerase activity and the breaks produced. Resistance can be caused by reducing the target topoisomerase e.g. downregulation of topo 2 as a defence against doxorubicin
Cells still need to have topoisomerase activity or their DNA would get tangled and break in an uncontrolled way
Needs to be compensated by an increase in topo I (and hence greater sensitivity to e.g. topotecan)
How do mutations effect in targets in drug resistant tumours
Cells may become resistant by mutation of the target
CML results from the fusion gene product; BCR-ABL, a tyrosine kinase that drives the malignancy
The molecular targeted drug, Gleevec/imatinib inhibits ABL-kinase
Gleevec is effective and non toxic
However 15% chronic phase and 100% advanced phase cases relapse
Most commonly this is due to mutations in kinase domain, which prevent binding of Gleevec but do not result in reduced kinase activity
Dasatinib was developed to overcome this resistance by binding to an alternative site – but mutations in ABL can confer resistance to this bullet
