Hormonal treatments of cancer Flashcards
Describe the drug palbociclib
It is a selective CDK4 and CDK6 inhibitor approved for treating hormone receptor-positive HER2-negative breast cancer COMBINED with endocrine therapy
(It targets the cell cycle)
palbociclib inhibits cell growth and suppresses DNA replication
Give examples of Topoisomerase I inhibitors
Camptothecins
topotecan
Irinotecan
Give examples of Topoisomerase II inhibitors
Anthracyclines
Epipodophyllotoxins
Where are steroid hormones synthesised from?
Cholesterol
Where is the aromatase enzyme stored?
Adipose and hepatic tissue
How do postmenopausal women receive oestrogen (endogenous)?
Through the conversion of androgens by the aromatase enzyme
Aromatase inhibitor mechanism of action
Inhibits the aromatase enzyme which reduces the production of oestrogen
Explain the 2 types of aromatase inhibitors
Type 1 inhibitors (androgen analogues) they bind irreversible to aromatase
Type 2 inhibitors contain a functional group that binds to the heme iron of the cytochrome p450 which interferes with the hydroxylation reactions.
Give examples for the 2 types of aromatase inhibitors
Type 1 inhibitors exemestane
Type 2 inhibitors anastrozole
State a type 1 aromatase inhibitor
Exemestane
State a type 2 aromatase inhibitor
Anastrozole
Selective oestrogen receptor modulators (SERMs) examples
Tamoxifen
Raloxifen
Tamoxifen moa
Tamoxifen binds to the ER at the ligand binding site.
(partial agonist)
Competitevely binds to the ER and adopts a different conformation that is dimerised and translocated to the cells nucleus
It binds to the DNA forming a new complex that has partial functions.
AF1 is active (AF2 domain doesn’t function)
Partial coactivators recruited
= partially inactivated transcription
How does tamoxifen have mixed activity?
It activates ER in the liver and uterus
It acts as an antagonist in breast tissue
Give an example of a selective receptor down-regulator
Fulvestrant
Fulvestrant moa
Binds to the ER monomers
inhibiting receptor dimerisation = blocking nuclear localisation of the receptor
Fulvestrant- ER complex that enters the nucleus is ‘transcriptionally inactive’ as AF1 and AF2 are disabled
= Fulvestrant - ER complex its unstable = accelerated degradation of the ER protein
What is an apocrine gland?
A specialised exocrine gland in which a part of the cells cytoplasm breaks off releasing the contents
Explain the differences between endocrine and exocrine glands
Exocrine glands secrete substances out onto a surface of a cavity through a ductal structure
Whereas
Endocrine glands secrete substances directly into the blood stream
Oestrogen function in the normal breast
(oestrogen is involved in cellular proliferation and differentiation)
Oestrogen allows the maintenance of mammary gland tissue
It primes tissue for the effects of progesterone during pregnancy for milk production
What is breast cancer?
Breast cancer occurs when abnormal cells in the breast begin to grow and divide uncontrollably leading to tumour formation
Where does breast cancer usually start?
In the breast tissue (commonly in cells that line the milk ducts of the breast)
majority of breast cancers arise from the luminal cells (that express ER)
Ductal breast carcinoma in situ (DCIS) vs lobular breast carcinoma in situ (LCIS)
DCIS - When cancer develops in ducts (that carry milk to the nipple) but remain within ducts ‘in situ’
Cancer cells have not yet spread outside the ducts into surrounding tissue
LCIS - abnormal cells form in the lobules (milk-producing glands) of the breast
*isn’t cancer but indicates an increased risk of developing breast cancer
Main function of the prostate gland
It produces prostatic fluid that creates semen when mixed with sperm produced by the testicles
AR (androgen receptor) function in the normal prostate
Androgens regulate prostate cell division and development
Which grading system is used to evaluate the prognosis of men using prostate biopsy samples?
Gleason grading system
Sample is examined by histology
Give an example of an androgen biosynthesis inhibitor
Abiraterone
It inhibits the production of androgenic pre-cursors
Abiraterone MOA:
It inhibits adrenal androgen production (disruption in adrenal synthesis) = decreased levels of serum testosterone
Testosterone synthesis inhibitors
& moa
Goserelin -> Super agonist
Abarelix -> Antagonist
They depress testosterone production
Abarelix moa
Abarelix = Antagonist
It blocks the GnRH in the pituitary gland = decreased LH = sustained suppression of testosterone release
What mechanism drives prostate growth and function?
Testosterone is converted in the prostate cells to a more potent form = dihydrotestosterone (DHT)
DHT binds to the androgen receptor = receptor dimerisation = translocation into the nucleus = binds to DNA = coactivation of machinery stimulation gene transcription = cell growth
5 alpha reductase inhibitors moa
5 alpha reductase converts testosterone into DHT
Inhibits the conversion of testosterone into dihydrotestosterone (= inhibits tumour growth)
Examples of 5 alpha reductase inhibitors
Finasteride
Dutasteride
(asteride)
When are 5 alpha reductase inhibitors mainly used?
They are commonly used for benign prostate hyperplasia
Examples of androgen antagonists
Bicatutamide
Flutamide
(-amide)
Androgen antagonists moa
It inhibits androgens (DHT) from binding to the receptor (AR) at the ligand binding site.
= inactivation of the receptor
