LECTURE 24: ANTICANCER

Question 1

• Cancer is defined by two heritable properties:

Answer 1

i. Cells proliferate without restraint
ii. Cells invade and colonize spaces normally reserved for other cells

Question 2

Outline the main treatment options for cancer

Answer 2

Surgery
* Removal of tumour tissue
* Difficult to ensure that the whole tumour is removed
* What if the tumour has metastasized?
Radiotherapy
* Generally targeted to tumour area
* Severe side effects
* What if tumour has metastasized?
Chemotherapy
* Treats whole body (including metastases)
* Severe side effects due to low therapeutic index
* Usually used in conjunction with surgery or radiation to
ensure tumour (and metastases) are completely
removed
Immunotherapy
* Stimulates the immune system to fight the cancer, typically by targeting tumour antigens

Question 3

Outline the major reason for the severe side effects of cancer drug therapies

Answer 3

Cancer cells are host cells, just out of control
* The most obvious difference is that tumour cells divide uncontrollably
* Drug ‘selectivity’ is due to greater accumulation in rapidly dividing cells
* Cells at the centre of a tumour may not be dividing
* Normal cells that divide rapidly (e.g. bone marrow) are hit with adverse effects that can cause significant damage

Question 4

genotoxic agents are

Answer 4

drugs that affect DNA integrity by directly targeting DNA

Question 5

3 types of genotoxic agents

Answer 5

1. intercalating agents
2. alkylating agents
3. enzyme inhibitors

Question 6

Intercalating agents

Answer 6

• These drugs wedge themselves into the spaces between nucleotides in DNA to interfere with transcription, replication and induce mutations

Question 7

Intercalating agent eg

Answer 7

doxoribucin

Question 8

Alkylating agents (The OGs)

Answer 8

• These are highly electrophilic compounds that react with nucleophiles in DNA to form strong covalent bonds (particularly N7 of guanine)
• This interferes with DNA replication and transcription, leading to mutations

Question 9

alkylating agents eg

Answer 9

cyclophosphamide

Question 10

enzyme inhibitors eg

Answer 10

topoisomerase I and II inhibitors

Question 11

Anti metabolites

Answer 11

drugs that target enzymes involved in dNA synthesis
- They are structurally similar to metabolites of these enzymes so are mistakenly processed as if they are the metabolites they resemble
- This prevents subsequent steps in DNA synthesis

Question 12

anti-metabolite eg

Answer 12

DNA polymerase inhibitors

Question 13

Spindle inhibitors

Answer 13

• Affect microtubule function - cell cannot divide and will die

Question 14

spindle inhibitors eg

Answer 14

paclitaxel

Question 15

how do spindle inhibitors works

Answer 15

• Paclitaxel is a spindle inhibitor that specifically targets tubulin to prevent polymerisation
• Cancer cells treated with paclitaxel have disrupted mitotic spindle assembly and chromosome segregation, blocking cell division
• Mitosis cannot progress, meaning there is prolonged activation of the mitotic checkpoint, triggering apoptosis (or causing the cell to revert to G0 phase of cell cycle without dividing)

Question 16

Endocrine interference eg

Answer 16

• Oestrogen antagonists or selective oestrogen receptor modulators (SERMs) can be used to treat oestrogen receptor positive breast cancer (including in males)

Question 17

intercalating vs alkylating agents

Answer 17

• Intercalation – drug slips between neighbouring base pairs of DNA, inhibiting DNA synthesis
• Alkyllating – react with DNA bases and prevent cell division by cross-linking two strands of the double helix