Resistance to chemotherapy

Question 1

Primary chemotherapy resistance

Answer 1

• Decreased drug activity, regardless of drug exposure.
• Also referred to as ‘intrinsic resistance’.

Question 2

Acquired chemotherapy resistance

Answer 2

• Resistance develops during or after the course of treatment.
• Drug-resistant cancer cells with secondary genetic modifications acquired during the course of therapy.

Question 3

Development of acquired resistance

Answer 3

• 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.

Question 4

Combatting acquired resistance

Answer 4

• Combination of chemotherapy drugs with different mechanisms of action.
• Tumour is unlikely to be resistant to several drugs.

Question 5

Mechanisms of metastases resistance

Answer 5

• Efficient repair to damaged DNA
• Decreased intracellular activation
• Increased intracellular breakdown
• Bypass biochemical pathways
• Overproduction of blocked enzyme
• Changes to receptor

Question 6

What is a cellular mechanism of defence, of a cancer cell, to alkylating agents?

Answer 6

Efficient repair to damaged DNA

Question 7

What is a cellular mechanism of defence, of a cancer cell, to methotrexate?

Answer 7

1. Decreased uptake by cell
2. Bypass biochemical pathways
3. Gene amplification/ overproduction of blocked enzyme

Question 8

What is a cellular mechanism of defence, of a cancer cell, to doxorubicin?

Answer 8

Decreased uptake by cell

Question 9

What is a cellular mechanism of defence, of a cancer cell, to vinca alkaloids?

Answer 9

Increased drug efflux

Question 10

What is a cellular mechanism of defence, of a cancer cell, to anthracyclines?

Answer 10

Increased drug efflux

Question 11

What is a cellular mechanism of defence, of a cancer cell, to 5-fluorouracil?

Answer 11

Decreased intracellular activation

Question 12

What is a cellular mechanism of defence, of a cancer cell, to cytarabine?

Answer 12

Increased intracellular breakdown

Question 13

Oncogene

Answer 13

• Gene that gains function when mutated
• Example = EGFR
  
  • Mutated EGFR = promotion of angiogenesis

Question 14

Tumour suppressor gene

Answer 14

• Gene that loses function when mutated
• Example = P53
  
  • Mutated P53 = suppresses apoptosis therefore promotes cancerous cell growth

Question 15

Multidrug resistance

Answer 15

Simultaneous resistance to many structurally and functionally unrelated drugs

Question 16

Causes of multidrug resistance

Answer 16

• 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

Question 17

ATP-dependent efflux pumps

Answer 17

Increased efflux = reduced intracellular concentration

Question 18

Upregulation of MDR1 gene

Answer 18

• Codes for p-glycoprotein (PGP)
• PGP increases drug efflux

Question 19

Deisgning a chemotherapy regimen

Answer 19

• Avoid drugs with similar MoA
• Choose drugs with complimentary MoA
• e.g. FEC

Question 20

FEC

Answer 20

• 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)

Question 21

Methotrexate (folate antagonist)

Answer 21

1. Inhibits dihydrofolate reductase (DHFR) - essential enzyme in folate metabolism.
2. Folate is an enzyme that maintains levels of tetrahydrofolate FH4.
3. Without tetrahydrofolate FH4, synthesis of DNA building blocks (dTMP) is inhibited.
4. Decreases DNA synthesis, repair and cell division.

Question 22

Methotrexate - resistance mechanism

Answer 22

• Overexpression of DHFR
• Uncontrolled proliferation of cancer cells

Question 23

Cisplatin (alkylating agent)

Answer 23

• 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)

Question 24

Cisplatin - resistance mechanism

Answer 24

• 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

Question 25

Herceptin (trastuzumab) - resistance mechanism

Answer 25

• HER2 (human epidermal growth factor 2) inhibitor
• Truncated receptors prevent antibody binding
• Upregulation of signal transduction pathways

Question 26

Lapatinib

Answer 26

• 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.

Question 27

Cell kill hypothesis

Answer 27

• 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