Pharm: reproductive antineoplastic drugs

Question 1

Tamoxifen

Answer 1

• Uses: breast CA (ER+ only) Rx, breast CA prevention in high risk groups
• Raloxifene also used for breast CA prevention
• Gets converted to hydroxymetabolites (active form) by CYP2D6
• Hydroxymetabolites bing to E2 receptor in antagonistic action in breast and agonistic action in uterus (SERM)
• May fail in those who are CYP2D6 poor metabolizers
• Antidepressents can inhibit CYP2D6 and should not be used w/ tamoxifen
• Side effects: hot flashes, prolonged Rx increases risk of endometrial CA and retinopathy

Question 2

Aromatase inhibitors

Answer 2

• Anastrozole and letrozole are used in ER+ breast CA Rx, are better than tamoxifen in postmenopausal women (not useful in premenopausal women b/c fail to inhibit E synthesis)
• They block conversion of androstenedione into estrone in adipose tissue and decrease E2 levels
• Also inhibit CYP3A4
• Side effects: hot flashes, increases risk of osteoporosis, CV problems, hypercholesterolemia

Question 3

GnRH agonists

Answer 3

• Leuprolide and goserelin are used to Rx prostate CA and endometriosis
• They continuously stimulate the GnRH receptor and cause its down regulation
• This leads to decreased LH release and subsequent decreased E and T in women/men
• In women they cause hypoestrogenism (hot flashes and osteoporosis)
• Initially they increase LH/T/E and can cause tumor flare

Question 4

Androgen synthesis inhibitors

Answer 4

• Abiraterone is used for metastatic castration: resistant prostate CAs that make their own T and become resistant to GnRH agonists
• Abiraterone inhibits CYP17 involved in conversion of pregnenolone and progesterone into T in both tumor and testes
• Leads to massive drop in T levels
• Side effects: cardiac toxicity, hepatotoxicity, hypertension

Question 5

Progestins

Answer 5

• Megesterol and medroxyprogesterone are used to Rx endometrial CA (more effective in PR+ tumors)
• They block E-mediated cell proliferation, inhibit E receptor gene expression and enhance degradation of E receptor
• Side effects: weight gain due to increase in appetite and fluid retention