Cancer chemotherapy 1

PH3115 Unit 2

What is the method of action of alkylating drugs?

Target DNA through alkylation. The alkyl groups are attached to good leaving groups to form a highly electrophilic intermediate used to attack the lone pairs on DNA. The addition of alkyl groups to DNA disrupts the hydrogen bonding

Name 5 alkylating agents

Dacarbazine

Busulfan

Cyclophosphamide

Chlorambucil

Thiopeta

What is the method of action of anthracyclines?

They are intercalating agents that inset themselves between DNA base pairs to distort structure. This disrupts replication and transcription so cancer cells cant divide. There is additional evidence that the sugar portion will inhibit topoisomerase enzymes to stop DNA unwinding to prevent replication

Name an anthracycline.

Doxorubicin

What is the major side effect of anthracyclines?

Dose dependant cardiotoxicity

Name a transition metal complex

Cisplatin

What is the method of action of transition metal complexes?

Binds to DNA to form cross links with the strands to distort the helix, preventing replication, transcription and division.

What is a serious effect of transition metal complexes?

Kidney damage

Name two second generation transition metal drugs

Carboplatin and Oxaliplatin

What types of cancer are transition metal complexes effective against?

testicular cancer

What structure do vinca alkaloids and taxanes effect?

Microtubules

Name a vinca alkaloid

Vincristine

Name a Taxane

Paclitaxel

What is the method of action of vinca alkyloids?

Prevent microtubule formation by binding to tubulin (component of microtubule)

What is the method of action of taxanes?

Stabilise microtubules excessively so they cant break down, preventing mitosis

Name a side effect of all cytotoxic drugs

Chemotherapy induces nausea and vomiting

Name cytotoxic drugs with a mild risk of emetogenic potential

• fluorouracil

• low dose methotrexate

• vinca alkyloids

Name cytotoxic drugs that have a moderate emetogenic potential

• taxanes

• low dose cyclophosphamide

• high dose methotrexate

Name cytotoxic drugs that have a high risk of emetogenic potential

• cisplatin

• dacarbazine

• high dose cyclophosphamide

What is the treatment for mild risk CINV?

dexamethasone

What is the treatment for high risk CINV?

dexamethasone and arepritant

What is the treatment for delayed CINV?

• dexamethasone

• rolapitant

• metoclopramide

What is the treatment of anticipatory CINV?

lorazepam

What is the generic name for HER2 positive breast cancer?

Trastuzumab

How does Herceptin (Trastuzumab) treat HER2 positive breast cancer?

Binds to the extracellular domain of HER2 to block HER2 signalling to stop division and growth

What is the serious side effect of biologics?

Anaphalaxis

What are the three components of antibody drug conjugates?

1. monoclonal antibody

2. linker

3. cytotoxic drug

What is the method of action of ADCs?

• binds to antigen on surface of cancer cell

• taken into the cell

• linker is cleaved by enzymes in the cell

• cytotoxic drug is released

What is the cytotoxic component of Brentuximab Vedotin?

monomethyl auristatin E (MMAE)

Give the treatments for oestrogen receptor positive breast cancer?

Tamoxifen

Anastrozole

Oestrogen is a SERM. What does SERM stand for?

selective oestrogen receptor modulator

What is the method of action of Tamoxifen?

Binds to oestrogen receptor blocking oestrogen signalling. It is an agonist or antagonist depending on the tissue it is targeting

What is the method of action of anastrozole?

Completely inhibits aromatase to reduce oestrogen production

What is the treatment for prostate cancer?

Enzalutamide

What is the method of action of Enzalutamide?

Blocks androgen receptor signalling that prevents tumour growth

What is the side effect of Enzalutamide?

Gynaecomastia

What drugs enhance the exposure of Enzalutamide?

• clopidogrel

• trimethoprim

• montelukast

What is thalidomide used to treat?

Multiple myeloma

What drug is a good example of drug repurposing?

Thalidomide

What is the method of action of Thalidomide?

1. anti angiogenesis

2. inhibition of IL6 (acts as a growth factor in myeloma cells)

3. activation of apoptosis

What is the usual suffix for tyrosine kinase inhibitors?

-tinib

Name a receptor that is targeted by tyrosine kinase inhibitors?

EGFR

What is the method of action of tyrosine kinase inhibitors?

Block kinase activity, preventing the kinase from transferring phosphate from ATP to internal protein to activate cascade that causing cell growth and proliferation.

what is synthetic lethality?

Where the breakdown of two repair pathway leads to cell death, but the breakdown of one is survivable.

Name three PARP inhibitors

Olaparib, Niraparib, Rucuparib

What mutation does a patient need to have to be illegible for PARP inhibitors?

BRCA

How does PARP usually function?

Binds NAD+:

• nicotinamide portion binds to the active site

• adenine dinucleotide (AD) forms protein bound polymer

What portion of NAD+ do PARP inhibitors mimic?

The nicotinamide portion