Chemotherapy

Question 1

What are the uses of chemotherapy

Answer 1

Primary induction treatment
- if it is the most effective modality - chemo can push to apoptosis
- if driven by the distribution of the disease - mets cannot all be removed by surgery so need a systemic action
Neo-adjuvant treatment
- to debulk tumour - too large to remove safely
- ahead of localised treatment - surgery or radiotherapy
Adjuvant
- after another modality
- mop up micro metastases
Regional treatment - chemo given to one region, upper limb a tourniquet in the arm to stop venous blood flow - circulate affected region only

Question 2

Uses of chemotherapy

Answer 2

Curative and palliative

Question 3

Malignant properties which can be targeted with chemotherapy

Answer 3

Apoptosis
Altered gene expression
Epigenetic modification

Question 4

Properties of malignant cells - cycle

Answer 4

Dysregulated cycle - checkpoints defect damage to genome
Either the cell goes into G0 phase for DNA repair or enters apoptosis
Cytotoxic chemo causes more damage to the DNA to push it into apoptosis via intact pathways
Relies on pathway being in tact if the are already damaged the chemotherapy will fail

Question 5

Properties of malignant cell - mitogenic signals

Answer 5

In particularly hormones
Oestrogen is necessary in breast cancers - block receptor reduce tumour growth
Can also be done with various cytokines and chemokines

Question 6

Properties of malignant cells - altered gene expression.

Answer 6

Genes may be switched on or off via methylation

Epigenetic

Question 7

Malignant properties - impaired apoptosis

Answer 7

There are drugs available to target proteins used during apoptosis

Question 8

Chemotherapy drugs can target different parts of the cell cycle

Answer 8

G1 phase - microtubule inhibitors, topiosomerase inhibitors - coiling and uncoiling DNA
Alkylating agents - cross links between DNA therefore causes direct damage to the DNA targets DNA synthesis
S phase - antimetabolites
Topiosomerase inhibitors
G2 phase - platinum analogues
M phase - microtubule inhibitors - cause dysregulation when chromosome pull apart from the spindle

Question 9

Apoptosis what can is be caused by

Answer 9

External signalling - such as Fas ligand TNFR family
Intrinsic factors DNA damage
Apoptosis can happen ‘immunosilently’ or be immunogenic
Immunosilent - prostatidyl serine signals to macrophages
Cell is phagocytosed silently with no immune stimulation
Immunogenic - calreticulin translocate to the cell surface triggering and immune reaction as it is expressed on MHC molecules - eat me

Question 10

Classes of chemotherapy drugs

Answer 10

Antimetabolites 
Anthracyclines 
Topiosomerase inhibitors 
Microtubule inhibitors 
Alkylating agents 
Platinum analogues 
Cytotoxic chemotherapy

Question 11

Anti-metabolites

Answer 11

E.g. 5-fluorouracil
Resembles pyramidine but has a fluorine on it
Gets taken up into a pathway
2 main mechanisms of action
- 5-FU converted to FUMP in Vivo, where is replaces uracil due to its similarity on shape so is incorporated into the cell but stops RNA processing and stops cell growth
- FdUMP inhibitors of thymidine synthetase which is responsible for making thymine nucleosides for use
Leads to a thymine deficiency in the cell, so it has to enter thymidine - deficiency induced apoptosis
Folate helps to stabilise the interaction between FdUMP so is often given alongside therapy

Question 12

Anthracyclines

Answer 12

Doxorubicin, daunorubicin, idarubucin, epirubicin
Planar molecules
Action - topiosomerase 2 inhibition, DNA intercalation ss and ds DNA breaks, free radical formation binds to DNA
Elimination - metabolism aldoreductases, binary excretion
Toxicity