Physiology 4 - Therapeutic Classes of Drugs for the Treatment of Cancer 2 (Woolard) Flashcards
What are the targeted therapies that can be used as anti-cancer agents?
- Monoclonal Antibodies
- Receptor Tyrosine Kinase Inhibitors
- Hormones
- Immunotherapy/Vaccine
What is Bevacizumab (Avastin)?
A monoclonal antibody that inhibits the role of VEGF by preventing its interaction at the extracellular receptor VEGFR1/2
What was Bevacizumab first FDA approved for treating?
Metastatic colorectal cancer (combined with 5- Fluoruracil)
Subsequently approved for treatment of lung cancer, renal cancer, glioblastoma
What are the consequences of VEGF inhibition (via monoclonal antibody such as Bevacizumab)?
IN TERMS OF TREATMENT
No production of NO or PGI2
Therefore inhibition of proliferation, migration, reduced permeability and survival.
No angiogenesis.
What are the consequences of VEGF inhibition (via monoclonal antibody such as Bevacizumab)?
IN TERMS OF SIDE EFFECTS
Hypertension Compromising wound healing and repair Arterial thromboembolic event Cardiac dysfunction Proteinuria / renal toxic effects
What is the role of VEGF in angiogenesis and how does Bevacizumab affect this?
Bevacizumab may play a role in ‘normalising’ the vascular structure, making vessels more susceptible to chemotherapy.
How does Bevacizumab cause hypertension?
VEGFR2 generates NO and PGI2 which induce vasodilatation, the blockage of VEGFR may lead to vasoconstriction.
This may also precede the onset of heart failure.
How does Bevacizumab cause arterial thromboembolic events?
VEGF has an important role in the homeostasis of platelets, this prevents their adhesion to the walls of vasculature.
Without VEGF, this adhesion may take place, leading to cardiac or cerebral ischaemia.
As a result, hemorrhage is also more likely in patients undergoing this treatment (in lung and GIST tumours).
How does Bevacizumab cause ventricular dysfunction and congestive heart failure?
VEGF maintains cardiomyocyte survival in response to stress or injury (this would include increase in peripheral vascular resistance or hypertension).
How does Bevacizumab cause adverse renal events?
Interaction of podocytes with VEGFR2 on glomerular endothelium is vital to normal function and repair.
Deletion of VEGF in podocytes results in EC damage, loss of podocytes and proteinuria
How does Bevacizumab cause wound complications?
ECs, platelets and coagulation cascade is disrupted by VEGF inhibitions
Problematic in patients undergoing surgery
What class of drug is Trastuzumab and where does it act?
HER2 Inhibitor; Monoclonal Antibody
A transmembrane tyrosine kinase inhibitor
What is HER2?
Human epidermal growth factor receptor 2
Over expressed in approximately 20% of invasive cancer phenotypes; its expression is associated with more aggressive disease and worse clinical outcome.
What are the side effects associated with Herceptin (Trastuzumab)?
Pain, GI disturbances and pulmonary symptoms.
Most significant limiting side effect; Cardiotoxicity
Risk Factors: Diabetes Mellitus Prior coronary artery syndromes Hypertension Pre-existing congestive heart failure
What was Herceptin first used to treat?
HER2+ breast cancer
What class of drug is Sunitinib?
Receptor Tyrosine Kinase Inhibitors
Inhibition of VEGFR2 - blocks c-KIT, FLT-3R, PDGFR and VEGFR signalling
Works further down, in the intracellular legs of the kinase at a tyrosine level
Prevents downstream signalling from PI3K, MAPK etc
What is Tamoxifen?
A hormone inhibitor of the ER (antagonist).
Who is Tamoxifen affect in?
Breast cancer patients that are ER+ and are post-menopausal
What are the associated side effects associated with Tamoxifen?
Hot flushes, nausea and vomiting
Sweating
Weight gain due to water retention
Long term use may increase incidence of endometrial cancer
What is the HPV Vaccine (Gardasil)?
Quadrivalent vaccine that protects against types 16 and 18 of HPV virus
What cancer can be caused by HPV virus (16&18)?
Cervical Cancer; in 70% of cancers
What are the side effects of Gardasil?
Headache, dizziness, sore muscles
Slightly raised temperature
Nausea and diarrhoea
Itching and a skin rash
What are the issues with Gardasil?
HPV 16/18 normally transmitted through sexual contact so in some societies it is a concern that it may encourage promiscuity (consider that it is offered to 12-13 year olds).
Inadequate information about duration of immunity.
Need for longer-term community surveillance.
Lack of inhibition of all types of HPV.
Doesn’t prevent incidence of cervical cancer in women already infected with HPV.
Therefore screening programs are still essential.
