Chemotherapy module 2

What are the 2 stages of the cell cycle?

1. Interphase: stage of growth prior to division (G1, S, G0, G2)

2. Mitosis: stage of cell division (Prophase, metaphase, anaphase, telophase, cytokinesis)

Describe the G0 phase

rest period, no cell division

Describe the G1 phase

Cells begin growing larger

Describe the S phase

Cells synthesis DNA

Describe the G2 phase

Cells grow even more and organise its contents in preparation for mitosis

Describe the M phase

cell division occurs (PMAT)

Describe prophase

DNA condenses forming chromosomes

Describe metaphase

nuclear membrane is gone and chromosomes are lined up in the middle of the cell

Describe Anaphase

Chromosomes are pulled to opposite ends of the cell by spindle fibres

Describe telophase

Two new nuclear membranes are formed around the two pairs of chromosomes

Describe cytokinesis

The cytoplasm is split forming two new identical daughter cells

Definitive

primary/sole treatment

Adjuvant

treatment given before the main treatment to improve the outcome

Neoadjuvant

Treatment given after the main treatment to reduce risk of recurrence of the disease

Salvage

Treatment given after the main treatments have failed to remove the residual disease

Dose intense regimes

higher doses of cytotoxic drugs per cycle while maintaining the standard cycle intervals

Dose dense regimes

Uses higher doses of cytotoxic drug doses while decreasing the interval between each cycle

Alkylating agents MOA (cyclophosphamide, ifosfamide)

attaches an alkyl group to DNA resulting in DNA strands breaking, mispairing, and sticking together resulting in DNA synthesis inhibition causing cell death

Platinum compounds MOA (cisplatin, carboplatin)

Binds to nitrogen atoms forming cross links (ties DNA parts together) preventing DNA synthesis causing cell death

CIsplatin main area of toxicity

Nephrotoxicity as it is secreted by renal tubules

Oxaliplatin main area of toxicity

sensory neuropathy

Antimetabolites 2 main MOA

Pretend to be chemical pieces called metabolites and cause cell death by:

1. Sneaking into DNA as they look nearly identical which results in DNA being unable to carry out synthesis causing cell death

2. Blocking important enzymes used in building DNA resulting in the prevention of DNA rather than having to directly damage DNA

Functions of metabolites

These help make:

• DNA

• Proteins

• Cell membranes

• Energy

What are the 2 main subtypes of antimetabolites?

1. Folic acid (VitB9) antagonist

2. Purine + Pyrimidine analogues

Folic acid (VitB9) antagonist MOA

• Blocks the action of folic acid by sneaking into cells as it looks similar to folic acid

• Blocks the enzyme dihydrofolate reductase (DHFR), which prevents the conversion of dihydrofolate into tetrahydrofolate which is essential for DNA synthesis

• Therefore cells cannot undergo DNA synthesis

Where do antimetabolites act in the cell cycle?

S phase mainly

Folinic Acid Rescue (Leucovorin)

Special form of folate which is able to bypass the blocked enzyme, dihydrofolate reductase (DHFR),

from methotrexate allowing non cancerous cells to recover and synthesis by restoring folate in them

Purine analogues MOA

Mimics A or G purines which are inserted into DNA resulting in faulty DNA causing cell death

Pyrimidine analogues MOA

Mimics C, T, and U, blocking enzymes required to create thymidine resulting in DNA being incomplete causing cell death

Topoisomerase

Enzyme which is responsible for preventing supercoiling of DNA by cutting it where it is tangled then resealing it

Topoisomerase inhibitors MOA

prevents the enzyme topoisomerase from resealing DNA after it has been cut resulting in DNA damage then cell death

Topoisomerase I Inhibitors MOA

prevents resealing of single strand DNA cuts

Topoisomerase II Inhibitors MOA

prevents resealing of double strand DNA cuts

Key toxicity of anthracyclines

cardiotoxicity due to the release of free radicals which cause damage to the cellular membrane of cardiomyocytes

Anthracyclines MOA

Insert themselves between DNA bases and interfere with topoisomerase II

Key toxicity of epipodophyllotoxins

Bone marrow suppression/myelosuppression (low RBC, white bloods cells, platelets)

Epipodophyllotoxins MOA

Prevents Topoisomerase II from resealing DNA after its cut, causing DNA damage to accumulate causing cell death

Tubulin Inhibitors MOA

Inhibit the action of microtubules to prevent cell division

What phase do tubulin inhibitors act in?

M phase

Vinca Alkaloids MOA

Prevent microtubules from forming by preventing polymerisation of tubulin (protein which microtubules are made up of) resulting in cell division stopping in metaphase

Taxanes + Epothiolones MOA

Freezes microtubules preventing them from breaking down (normally the build then break down) resulting in dysfunctional mitotic spindles causing cell division to stop

Targeted Therapy

They act on specific molecular targets and signalling pathways associated with cancer cells. Only useful in pts who tumour has a specific gene mutation that codes for that target.

Small molecular drugs

small chemical compounds that are able to cross the cell membrane to enter cancer cells and target enzymes or DNA processes

Large molecular drugs

Large proteins that are unable to cross the cell membrane so they work by binding to targets on cancer cells to exert their effects

Monoclonal Antibodies MOA (Large molecular drugs)

1. Recognise and attach to one specific antigen on cancer cells 

2. Block growth signals on the receptor of cancer cells preventing them from receiving growth signals

3. Marks the cancer cell for our immune system to attack and destroy the cell 

4. Some antibodies carry the drug directly to the cancer cell which reduces damage to normal cells

Tyrosine kinase Inhibitors (TKIs) MOA (Small molecular drugs)

1. TKIs enter the cell membrane

2. Bind to the ATP binding site of tyrosine kinase (enzyme which is overactive in cancer cells) preventing it from working

3. Cancer cells would use this ATP for energy to active growth signals but without it the signalling pathway is blocked

4. Cancer cells cannot undergo replication causing apoptosis

Angiogenesis Inhibitors MOA

1. Cancer cell releases vascular endothelial growth factor (VEGF) to stimulate vessel growth

2. Drug blocks VEGF or the receptor

3. VEGF is unable to activate the receptor on endothelial cells

4. New blood vessels cannot form to grow towards the tumour

5. Tumour becomes starved of oxygen and nutrients preventing tumour growth

MAPK Pathway (RAS-RAF-MEK-ERK)

Controls cell growth and proliferation

PI3K-AKT-mTOR Pathway

Controls cell survival (AKT a key protein that prevents cancer cells from cell programmed death), metabolism, and growth

Immune checkpoint inhibitors (ICIs)

Subset of monoclonal antibodies that BLOCK inhibitory pathways in T cells allowing our immune system to recognise and attack cancer cells

MOA of PD-1

Expressed on the surface of T cells and acts as a ‘off switch’ which can be used by healthy cells to downregulate T cells when they become overactive and start attacking healthy cells

How is PD-1 activated?

Normal cells will have a complementary molecule on their surface called PD-L1 which will bind with PD-1 on T cells causing them to ‘off’.

MOA of action of ICIs which target the PD-1 pathway

These drugs bind to PD-1 receptors on T cells preventing tumour cells with PD-L1 ligand from binding with it to ‘off’ its response.

MOA of action of ICIs which target the PD-L1 pathway

These drugs bind to PD-L1 on tumour cells preventing binding of PD-L1 to PD-1.

What 2 signals must be received in order for T cells to be activated?

1. Antigen recognition: T cell receptor (TCR) binds antigen MHC 

2. Co stimulation: CD28 on T cells binds to B7 (CD80/86 on antigen presenting cells) = T cell activation

CTLA-4 MOA

When CTLA-4 binds to B7 (CD80/86) it blocks CD28 stimulation which results in an inhibitory signal being sent to the T cell. This results in inhibition of T cell activity as CTLA-4 is responsible for stopping overactivation of the immune system.

CTLA-4 in cancer cells

Cancer cells exploit this pathway by promoting inappropriate CTLA-4 signalling to inhibit T cell activity, allowing them to survive and proliferate.

CTLA-4 inhibitors

Blocks CTLA-4 causing CD28 to bind to B7 allowing activation of T cells to recognise and attack cancer cells.

Hormonal therapy

mainly targets male and female hormones androgens and oestrogens as some cancer types are driven to grow by the presence of particular hormones

What are the 4 main classes of hormonal therapy?

1. Anti-androgens

2. Aromatase inhibitors

3. Gonadotropin-releasing hormone (GnRH) agonist

4. Selective Oestrogen Receptor Modulators (SERMs)

Hormonal therapy: Anti-androgens

Mainly block or inhibit androgens such as testosterone and dihydrotestosterone (DHT)

Anti androgen MOA: Inhibition of androgen synthesis

Reduces the amount of testosterone made by acting on the hypothalamic pituitary gonadal axis causing LH suppression. This suppression prevents synthesis of testosterone.

e.g. Abiraterone

Anti androgen MOA: Inhibition of 5a reductase

Prevents 5a reductase, an enzyme responsible for converting testosterone to DHT, resulting in low DHT levels which is helpful in preventing prostate growth

e.g. Finasteride

Anti androgen MOA: Androgen receptor blockade

Directly blocks androgen receptors which stops testosterone and DHT from binding to these receptors. Therefore, cells do not respond to them causing a reduction in male characteristics such as less hair and decrease prostate growth

e.g Bicalutamide, spironolactone

Anti androgen MOA: Suppression of androgen release

Suppression of LH secretion which results in medical castration due to decreased testosterone synthesis

Hormonal therapy: Aromatase Inhibitors

Targets aromatase which is an enzyme responsible for converting androgens into oestrogen. Prevention of this convertion results in decreased levels of oestrogen

Hormonal therapy: 2 types of Aromatase inhibitors

1. Non-steroidal (reversible inhibitors: Binds temporarily to aromatase to inhibit its enzyme activity 

• E.g. letrozole 

2. Steroidal (irreversible inhibitors): Acts as a false substrate (molecule an enzyme acts on which gets converted to a product) and permanently inactivates aromatase 

• E.g. Exemestane

Hormonal therapy: Gonadotropin-releasing hormone agonist (GnRH)

Mimics the natural GnRH but the effect depends on how the drug is administered:

GnRH agonist: Initial stimulation (Flare effect)

When first given they stimulate GnRH receptors causing a temporary increase in testosterone and oestrogen

GnRH agonist: Continuous use = Suppression

Continuous administration results in GnRH receptors becoming desensitised and downregulated causing a decrease in testosterone and oestrogen.

Hormonal Therapy: Selective Oestrogen Receptor Modulators (SERMs)

Binds to oestrogen receptors and act as either antagonist or agonist depending on the tissue:

1. Antagonists: Blocks oestrogen effects in specific tissues

2. Agonist: mimics oestrogen in specific tissues

Pharmacodynamics (PD)

What the DRUG does to the body

PD Interactions

1. Synergistic Interactions: Drugs which are combined produce a greater effect, resulting in increased anti-cancer activity 

2. Additive Interactions: Combination of drugs results in increased toxicity 

3. Antagonistic Interactions: Combination of drugs results in reduced effectiveness

Pharmacokinetics (PK)

What the BODY does the drug

PD (ADME)

1. Absorption: Movement of the drug from the site of administration into the bloodstream and is affected by the route:

• Oral, IV, IM

2. Distribution: Movement of the drug from blood into tissues and is affected by:

• Protein binding 

• Tissue perfusion 

• Lipid solubility 

3. Metabolism: 

• Modification of the drug mainly in the liver 

• Cytochrome P450 (CYP450) which are enzymes in the liver responsible for metabolising >90% of drugs 

4. Excretion/elimination: 

• Removal of drugs from the body via the kidneys mainly