Week 3: Reproductive antineoplastic drugs

Question 1

Tamoxifen

Answer 1

• anti-estrogen
  1. use: early stage breast cancer after surgery to prevent recurrence, advanced stage or metastatic breast ca., prevention of breast Ca. in high risk women
  2. pharmacokinetics
• parent drug and hydroxymetabolites (high affinity) bind to ER. long half life=2weeks
• ER+/PR+ responds best
  3. SERM
• antagonist in breast, agonist in uterus

Question 2

Factors that affect tamoxifen metabolism

Answer 2

1. genetic polymorphism
   - tamoxifen is metabolized by CYP2D6 to hydroxy metabolites
   - poor metabolizers have increased risk of breast cancer recurrence (controversial)
2. . anti-depressants
   - inhibits CYP2D6. Less active metabolite. Use Venlafaxine instead of paxil (Paroxetine) or prozac (fluoxetine).
   - anti depressants given for depression and hot flashes

Question 3

Anastrozole and Letrozole

Answer 3

• aromatase inhibitors
  1. mechanism
• prevents conversion of androgen to estrogen in adipose tissue
• only good for postmenopausal women
• in premenopausal women: negative feedback increases aromatase activity and increases estrogen levels in ovary to compensate.
  2. Adverse
• induces hot flashes and osteoporosis
• inhibits cytochrome p450
  3. switch therapy
• 2-3 years tamoxifen, and 2-3 years of aromatase inhibitors

Question 4

Leuprolide and Goserelin

Answer 4

• GnRH agonist
• desensitization due to continuous stimulation of receptors
• uses: prostatic cancer, endometriosis
• can cause vasomotor symptoms and osteoporosis. Add back regimen- add estradiol and medroxyprogesterone

Question 5

Flutamide

Answer 5

• anti-androgen
• converted to hydroxyflutamide in liver
• hepatotoxic at high concs.
• not used in mono therapy
  1. mechanism:
• blocks androgen receptor
• unwanted effect: however, it removes negative feedback., results in increases in testosterone.
• used with GnRH agonist-decreases testosterone, overcomes unwanted effect

Question 6

Abiraterone

Answer 6

• androgen synthesis inhibitors
• metabolized by CYP 3A4
• blocks CYP7 17a-hydroxylase and CYP17 C17,29-lyase

Question 7

Progestins for endometrial cancer therapy

Answer 7

• megestrol acetate and medroxyprogesterone
• used to treat endometrial ca., for cancers of PR+
• mechanism: blocks estrogen stimulated cell proliferation, inhibits ER expression, enhances degradation of ER
• resistance: progestin promotes loss of PR

Question 8

List of drugs -reproductive antineoplastic

Answer 8

Antiestrogens: Tamoxifen
Aromatase inhibitors: Anastrozole and letrozole
GnRH (LHRH) agonists: Leuprolide and goserelin
Antiandrogens: Flutamide
Androgen synthesis inhibitors: Abiraterone
Progestins: Megesterol & medroxyprogesterone