PY6010

Chemotherapeutic Agents
& Drug Discovery

Lecture 6
Hormone-Dependent Cancer Therapy
Professor Fawaz Aldabbagh
 Sex Hormones
Androgens

Progestins Oestrogens

• Androgen receptor (AR) is activated by the binding of any androgenic hormone.

• DHT is a considerably more potent agonist of AR than testosterone.
• DHT levels are particularly high in the prostate gland, where 5-reductase expression is high.
• DHT levels circulating in the body are otherwise low (5-10% that of testosterone).
• AR is closely related to the progesterone receptor and high doses of progestins can block AR.
• Androgens are precursors to estrogens for men and women.
• Androgens are synthesized in the testes, ovaries and adrenal glands.
• Estradiol is the major female sex-hormone
• Estradiol is synthesized in the follicles of the ovaries, the testicles, adrenal glands and liver.
 Prostate Cancer: Hormone Therapy
• Prostate Cancer requires Androgens to Grow
• As the prostate enlarges Prostate Specific Antigen (PSA) levels rise
• Selective Antagonists for AR (stops prostate cancer cells growing) include

Flutamide, Cyproterone Acetate and Bicalutamide

• Androgen Deprivation Therapy: Reduce androgen formation by shrinking the tumour; an alternative to surgery
 Androgen Deprivation Therapy using Non-Steroidal Antiandrogens

Prodrug, relatively short-duration time, so taken multiple times per day

Antiandrogens also used to treat androgen-dependent conditions

R-isomer is the active form

Non-steroidal antiandrogen used to treat androgen dependent conditions,
Feminisation & Transgender treatments
Some common side effects for men who receive hormone therapy for prostate cancer include:
Hot flushes, loss of ability to have sex, weakening of bones, nausea, enlarged and tender breasts and fatigue.
 Prostate Cancer: Steroidal Therapy Treatments

Estramustine
Estradiol Estrone
Dual Estrogen Ester (Prodrug) and Nitrogen Mustard
None are cures for prostate cancer but can significantly extend life-span
Similar side-effects

Carbamate is EWG

Cyproterone Acetate
(Trade name: Androcur)
Estramustine Phosphate Progestin Related Antiandrogen

Palliative treatment of metastatic or progressive prostate cancer

Weak DNA alkylation agent (similar to chlorambucil)
Strong suppression of androgen production
Estrone is the final metabolism product
 Breast Cancer: Hormone Therapy using Tamoxifen
• Estrogen helps breast cancer cells to grow: Receptor Positive (ER+) – tested by biopsy
• Antagonist, BUT is a Selective Estrogen-Receptor Modulator (SERM)
• OR partial agonist for the endometrium and linked with endometrial cancer (carcinogenic)
• FDA approved for the prevention and treatment of breast cancer (including in men)
• Prodrug with little affinity for the protein, it is metabolised in the liver into the active metabolites

Tamogel is an active metabolite

& potential topical treatment for breast cancer
 Breast Cancer in Post-Menopausal Women

• After the menopause, women (ER+) don’t produce estrogen from their ovaries.
• But small amounts are produced using aromatase enzymes.
• Aromatase convert androgens into estrogens within fatty tissue, muscle and skin

– Aromatase Reversible Competitive Inhibitors:

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

N
N
N CN
N
N
1,2,4-triazoles
N

NC CN
CN

anastrozole letrozole
 Learning Outcomes

• I can identify the main sex hormones and I know their physiological roles.
• I know that the 5α-reductase and dihydrotestosterone (DHT) levels are high in the prostate.
• I know DHT is a potent agonist for the AR.
• I can briefly explain hormone deprivation therapy for prostate cancer.
• I know the main androgen deprivation therapy steroidal and non-steroidal drugs.
• I know the structure-activity of Estramustine and the function of the carbamate group.
• I can briefly describe the use of Tamoxifen in breast cancer and identify the metabolite active form.
• I understand the role of aromatises and aromatise reversible competitive inhibitors for post-menopausal
cancers.
• I am aware of the significance of stereochemistry and geometric isomers for the main drugs.