Hormone Dependant Cancer Treatments

Question 1

What are main sex hormone and their physiological roles? Where are they synthesised?

Answer 1

androgens = are synthesised in the testes, ovaries and adrenal glands
- testosterone
- dihydrotestosterone
- androstenedione

progestins
- progesterone

oestrogens = are synthesised in the follicles of ovaries, testicles, adrenal glands and liver
- estradiol

androgens are precursors to oestrogens
- testosterone is converted to oestrogen via aromatisation of the A ring (not DHT)

Question 2

How are testosterone and dihydrotestosterone related?

Answer 2

dihydrotestosterone is more potent than testosterone
- converted from testosterone to DHT by 5-alpha reductase

DHT levels are high in the prostate gland where 5-alpha reductase is high but levels circulating the body is low
- testosterone levels are higher

DHT differs from testosterone structurally by only a single hydrogen atom at C5

Question 3

How are androgen receptors activated?

Answer 3

androgen receptors are activated by the binding of any androgenic hormone

androgen receptors are closely related to the progesterone receptor
- high doses of progestins can block the androgen receptor

Question 4

What is hormone deprivation therapy for prostate cancer?

Answer 4

ADT is designed to either stop testosterone from being produced or to directly block it from acting on prostate cancer cells
- shrinks the tumour

Question 5

What are the main androgen deprivation therapies?

Answer 5

non-steroidal therapy
- selective antagonists for androgen receptor
= flutamide and bicalutamide

steroidal therapy
- estradiol, estrone and estramustine
- cypterone acetate

Question 6

How does flutamide act?

Answer 6

non-steroidal therapy

is metabolised to its active form
- oxidation of C3 which adds a hydroxyl group

selective antagonist of the androgen receptor (AR)
- competing with androgens like testosterone and dihydrotestosterone (DHT) for binding to ARs in tissues

Question 7

How does cyproterone acetate work?

Answer 7

steroidal therapy

is metabolised to its active form
- oxidation which adds a hydroxyl group
= has a chiral centre so R-enatiomer is the active form

selective antagonist of the androgen receptor (AR)
- competing with androgens like testosterone and dihydrotestosterone (DHT) for binding to ARs in tissues

Question 8

What are common side effects for men who receive hormone therapy for prostate cancer?

Answer 8

hot flushes
loss of ability to have sex
weakening of bones
nausea
enlarged and tender breasts
fatigue

Question 9

How does estramustine work?

Answer 9

is a prodrug
- active form is an oestrogen agonist and weak alkylating agent
= is an alkylating agent due to the presence of a nitrogen mustard

nitrogen is weakly nucleophilic due to EWG carbamate
- cannot substitute chloride ion to produce aziridinium ion
- reacts with DNA by directly displacing the chloride ion

androgen suppression vis metabolism to estradiol and estrone

Question 10

What is tamoxifen? How does it work?

Answer 10

is a prodrug
- metabolised to 4-hydroxytamoxifen via hydroxylation on the benzene ring
= active metabolite is afimoxifene/tamogel

acts via two mechanisms
antagonist
- selective estrogen receptor modulator (SERM)

partial agonist for the endometrium

Question 11

What is tamoxifen used to treat?

Answer 11

oestrogen receptor positive (ER+) breast cancer

Question 12

When are aromatase reversible competitive inhibitors used?

Answer 12

are used after menopause
- women do not produce enough oestrogen from their ovaries but small amounts are produced using aromatase enzymes

aromatase enzymes convert androgens to oestrogens within fatty tissue, muscle and skin

Question 13

How do aromatase reversible competitive inhibitors work? What are the different types?

Answer 13

bind at the CYP450 subunit of the enzyme and prevent estrone formation

anastrozole and letrozole