CPTP 3.7 Anti-Cancer Drugs Flashcards
Name the cytotoxic drug classes used in the treatment of malignant disease. Give one example from the formulary of each.
Alkylating agents
• Cyclophosphamide
Anthracyclines
• Doxorubicin
Antimetabolites
• Methotrexate
Vinca alkaloids
• Vincristine
Platinum compounds
• Cisplatin
What were alkylating agents developed from?
Mustard gas
What structure are alkylating agents?
What does this allow them to do (mechanism of action)?
Bischloroethylamine: They have a central N atom, bound to two chloroethane groups and one variable group (worth looking up)
Forms a DNA crosslink preventing DNA replication:
• The Cl atoms are displaced, and the two ethyl ‘arms’ grab onto the two unzipped replicating strands
• One replicating strand is grabbed by each arm (I.e. one onto the lagging strand and one onto the leading strand), so that they can no longer be copied into daughter DNA. (IMG 1)
Name an alkylating agent.
Cyclophosphamide (IMG 2)
What is the mechanism of action of anthracyclines? Recall the formulary example.
Topoisomerase I/II inhibitors:
• Topoisomerase II usually ‘untangles’ DNA, while topoisomerase I usually breaks once strand to relieve torsion
• Anthracyclines stabilise the complex between the topoisomerase enzymes and DNA
Doxorubicin
What are the side effects present in all chemotherapy options?
All (affects rapidly-dividing cells): • Bone marrow suppression • Hair loss • Nausea • Loss of fertility • Teratogenic effects • Fatigue
How does the side effect of bone marrow suppression manifest?
- Neutropenia
- Anaemia
- Thrombocytpenia
In which chemotherapy options should extravasation be avoided?
- Doxorubicin
* Vincristine
what can the cardiotoxicity of doxorubicin lead to and how is this assessed?
Late heart failure
Heart ultrasound (echocardiogram) every 5 years for people who have been treated with doxorubicin
What is the mechanism of the cardiotoxic effects of doxorubicin?
Induces apoptosis in the cardiac stem cells, so the regenerative capacity of the heart is reduced
Name an antimetabolite and state how it works
Methotrexate
Inhibits pyramidine and purine synthesis, inhibiting DNA replication:
• It does this by inhibiting dihydrofolate reductase (DHFR) by mimicking the structure of its substrate, folate.
• The metabolite of DHFR (folonic acid) is needed to build purines and thymidine (pyramidine)
What must be given along with methotrexate? Why?
Folinic acid, a lethal dose of methotrexate is given, so the metabolite (folonic acid) must be given as an antidote
How does methotrexate maintain its therapeutic efficacy despite the administration of the antidote, folonic acid?
Cancerous cells are more sensitive to methotrexate than regular cells
What is commonly used in conjunction with methotrexate to maximise remission?
- Vincristine
* 6-mercaptopurine
Why does remission occur with leukaemia when methotrexate is used to treat it? How is this worked around?
Meningeal leukaemia occurs because the blood brain barrier forms a pharmacokinetic sanctuary. These cells survive and return to cause relapse
Intrathecal methotrexate injections are used
What is the effect of neutropenia?
Increased risk of infection
What is the effect of thrombocytopenia?
Increased risk of bleeding
Why must kidney function be tested before methotrexate use?
If methotrexate cant be excreted by kidneys, crystals of methotrexate form in the kidneys, damaging them. (and the liver)
Name a vinsa alkaloid. What do these do?
Vincristine
A ‘spindle toxin’ that inhibits mitosis by binding to tubulin
On top of the normal chemotherapy side effects, what are the side effects of vincristine?
Neurotoxicity:
• Neuropathic pain and numbness
• Drop foot
• Severe constipation
On top of the normal chemotherapy side effects, what are the side effects of methotrexate?
- Liver and kidney toxicity
- Skin rash
- Mucositis
On top of the normal chemotherapy side effects, what are the side effects of doxorubicin?
- Cardiotoxicity
* Mucositis
When should intrathecal injections never be used? Why?
When using Vincristine, as this is lethal
Which protein kinase pathway is most frequently abnormally activated in cancer cells?
Tyrosine kinases
Name a protein kinase inhibitor. Which type of cancer does it work on?
Imatinib
Chronic myeloid leukaemia
Describe the aetiology of chronic myeloid leukaemia
(IMG 3):
• Chromosome 9 usually has the ABL gene, which codes for a protein which is a key signalling molecule in cytokine receptor signalling
• Chromosome 22 usually has the BCR gene
• There is a translocation between chromosomes 9 and 22
• This results in chromosomes 9q+ and 22q-
• BCR and ABL are now both on 22q-
• BCR-ABL is constantly expressed as a result
• This leads to overexpression of the signalling pathway involving ABL
• This activity triggers proliferation
How does imatinib treat chronic myeloid leukaemia?
Binds to the ABL component of BCR-ABL, competitively antagonising ATP. This inactivates BCR-ABL.
What are the side effects of imatinib?
- Fatigue
- Loss of appetite
- Diarrhoea and vomiting
What are the non-cytotoxic cancer drug classes and an example of each?
Protein kinase inhibitors
• Imantinib
Sex hormones and antagonists:
• Tamoxifen
What is the link between sex hormones and cancers?
Oestrogen receptors (nuclear hormone receptors) are drivers of many breast cancers. These modify transcriptional activity.
How does tamoxifen work?
It is an analogue of oestrogen, so binds to oestrogen receptors, and stabilises them in a ‘repressor’ confirmation (represses transcription)
What are the common side effects of tamoxifen?
- Hot flushes
- Vaginal discharge
- Cataracts
- Oedema and leg cramps
- Menopause symptoms (irregular periods)
What are the main factors determining survival rate after cancers?
- Surgical resectability
* Sensitivity to chemotherapy
What can cause resistance to chemotherapy?
- Acquired resistance through clonal selection (due to the many different subclones, works the same way as evolution)
- However, some cancers are intrinsically resistant
Multidrug resistance phenotype:
• p-glycoprotein (a cellular efflux pump) which is usually expressed in the GI tract and brain, pumps all complex compounds out of the cell, including chemotherapy compounds
• This protein can be overexpressed in some cancer cells/subclones
What is the solution to chemotherapy resistance?
Combination chemotherapy
What can cause imatinib resistance?
mutations in BCR/ABL1 in some subclones
How is imatinib resistance counteracted?
By using analogues of imatanib (new generations of the drug) together with it
