Dr.

Harshika Patel
Pharmacology and therapeutics II
Date:14/05/2018
Time :2-4pm
 Growth of a number of cancer tumor either
dependent or regulated by hormones. Particularly,
Sex hormones and adrenocortical hormones

 Many essential hormones analogs yielded during

fertility, menopause and childbirth to treat breast and
prostate cancers (a/c reasearch)
 Molecules work by:
o Interrupt the stimulate axis  created by  systemic
pool of androgens and estrogens
o By inhibiting hormone production, or
o By binding to receptors,  ultimately, block the
complex expression of genes that promotes tumor
growth and survival
 can be effectively treated with sex hormone therapy or ablation of
appropriate endocrine organs.
 Proven: effective in extending survival , delaying or preventing
tumor recurrence (B/P cancers)
 The mechanisms of action: have been partially clarified ( B/P/
lymphoid cancers):
o Specific cell surface receptors have been identified for estrogen,
progesterone, corticosteroids, and androgens in neoplastic cells in these
tissues*
o steroid-sensitive cancers express specific cell surface receptors,
such as
 Prednisone-sensitive lymphomas,
 estrogen-sensitive breast cancers, and
 prostatic cancers express specific receptors for corticosteroids,
estrogens, and androgens, respectively.
 Possible to assay tumor specimens to steroid receptor contents
and identify whether the individual pt are likely to benefited from
HT or not?
 Breast, prostate and endometrium cancers
o With replacement doses: estrogens stimulate the breast
and endometrial cancer
o But at higher doses can suppress the tumor mass
(metastatic breast cancer )
o Largely replaced by antiestrogen agents
 Prostate cancer:
o Androgen stimulate the growth while estrogen
reduce the androgen production.
o Drugs which reduce the production of androgen or
block the effect of that hormones at receptor level
are also effective in prostate cancer.
Prednisolone :
 Marked lympholytic effect so used in acute
leukaemias (ALL) & lymphomas (which arose in pt
with cushing’s syndrom –hypersecretion of cortisol*)
MOA: prodrug
 Reduced to prednisolone form by 11-B-
hydroxysteroid dehydrogenase  bind to specific
receptor  trigger the production of specific protein
Resistance
 absence of the receptor protein or a mutation that
lowers receptor affinity for the hormone
 Some resistance cell complex form but express genes
are affected, apparently
PK:
 orally active, bound to plasma albumin and transcortin .
Metabolized in liver to form a active compound prednisolone,
latter glucuronidate and excreted in urine

 They Have :
– Anti-inflammatory effect
– Increase appetite, prevent anemia
– Produce sense of well being
– Increase body weight
– Supress hypersensitivity reaction
– Control hypercalcemia & bleeding
– Non specific antipyretic effect
– Increase antiemetic effect of ondansetron

AD: ulcer and pancreatitis

 Rare : hyperglycemia, cataract formation, glaucoma, osteoporosis,
and change in mood (euphoria or psychosis)
 Physiological antagonists of androgens
 largely replaced by the GnRH analogs because of
fewer adverse effects
 Thus used to antagonize the effects of androgens in
androgen dependent prostatic cancer

 Estrogens inhibit the growth of prostatic tissue by

blocking the production of LH  decreasing the
synthesis of androgens in the testis.
 Thus, tumors that are dependent on androgens are
affected

 AD: thromboemboli, myocardial infarction, strokes,

and hypercalcemia (severe)
 Men who are taking estrogen experinced
gynecomastia and impotence
 Fosfestrol
– Prodrug , phosphate derivative of stilbesterol
– 600-1200mg IV initially later 120-240 mg
orally

PK: orally active, plasma albumin bound form

(about 95 %), metabolised in intestine and liver
(liver enz cytochrome p450), excreted thru’ feces
and urine

Adverse effects: breast tenderness, headache, fluid

retention (bloating), nausea, dizziness, and weight
gain
-Structurally related
to synthetic
estrogen,
diethylstilbesterol
-Has weak
estrogenic activity

Fails to induce estrogen-responsive gene

Hence RNA synthesis doesn’t arise
 result is a depletion (down-regulation) of
estrogen receptors
 supressed the:
• growth-promoting effects of the natural
hormone
• other growth factors
 In premenopausal women the drugs prescribed
with GnRH analog (leuprolide)  decrease the
estrogen level
 Tamoxifen is not affect any phase of cell cycle

Resistance :
decreased affinity for the receptor or the presence
of a dysfunctional receptor.
 DOSE:10-20mg bd
 Standard hormonal treatment in breast cancer
 Prophylactic use in breast cancer (have ability to cause
premalignant lesion due to estrogenic properties, advice
to use only for 5 years )

 PK: orally active, metabolised in liver  some metabolised

have antagonised actions and some have agonist activity,
predominately excreted thr’ bile in the feces

Adverse effects:
 Hot flushes
 Vomiting
 vaginal bleeding
 menstrual irregularities
 venous thromboembolism
 Dermatitis
 rarely endometrial cancer
 Advance drug
 nonsteroidal triphenylethylene derivative Approved drug
for metastatic breast cancer in post menopause women
 Toremifene binds to estrogen receptors and may exert
estrogenic, antiestrogenic, or both activities, (same as
tamoxifen)
PK:
 orally active,
 plasma protein bound mainly albumin 92%
 Hepatic activation by enz CYP3A4 N demethyltoremifene,
which is also antiestrogenic but with weak in vivo
antitumor potency
 Excreted via bile in feces
 first agent approved by the U.S. FDA in the class of ER down
regulators
 Pure estrogen antagonist (has improved safety profile, faster
onset and long duration of action)

USES: Metastatic ER+ Breast Ca in postmenopausal women that

has progressed on tamoxifen

MOA:
 Drug bind with receptor and alter the structure of receptor.*
 Inhibits ER dimerization & prevents interaction of ER with DNA
 ER is down regulated resulting in more complete supression of
ER responsive gene function
PK:
 highly lipophilic, plasma protein bound drug
 Max plasma conc reached around 7 days with
i.m. administration and maintained over a month
 T1/2: 40 days
 Metabolism : by CYP3A4 , 17 keto compound
have anti estrogenic activity,
 Less than 1% parent drug excreted in urine

Dose: 250mg i.m. monthly

AD: nausea, asthenia, pain, vasodilation (hot

flashes), and headache
Injection site reaction may reduced by giving
injection slowly
“block the function of the aromatase enzyme that
converts androgens to estrogens”
 Considered as adjuvant rx of postmenopausal women
 hormone receptor–positive breast cancer
 Either by intial therapy or after temoxifen

 First generation AIs:

Aminoglutethimide
 Second generation:
Formestane, Exemestane
 Third gereration:
Anastrozole , Letrozole
 First, AI metastatic breast cancer in postmenopausal
women

 Inhibit both adrenal synthesis of pregnenolone

(precursor for estrogen) and extra adrenal synthesis

 Also inhibits hydrocortisone synthesis provoke

compensatory rise in adrenocorticotropic hormone
secretion devastate the blockade of the adrenal
taken with hydrocortisone

 Because of non selectivity , unfavorable side effects,

as well as the need to concomitantly administer
hydrocortisone  replaced by newer AIs
Imidazole AIs:
 more potent,
 more selective,
 need not to required hydrocortisone therapy,
 do not predispose endometrial cancer,
 less androgenic side effects

Letrozole
 Orally active non steroidal compound
 MOA : Inhibits aromatisation of testosterone &
androstenedione to form estrogen.
 Uses : Breast Ca- & adj. to mastectomy
 Dose :2.5mg bd orally

Anastrozole : • Second line drugs for

hormone dependent BC
 1mg OD in ER+ Breast Ca
after temoxifen in U.S. in
 A/E : hot flushes other country first line drug
for postmenopause BC
• Liver metabolism occurred
 A steroidal, irreversible inhibitor of
aromatase,
 orally well absorbed and widely distributed.
Hepatic metabolism is by the CYP3A4
isoenzyme,
 Because the metabolites are excreted into the
urine doses of the drug must be adjusted
in patients with renal failure.
 major toxicities are nausea, fatigue, hot
flashes, Acne.
FLUTAMIDE & BICALUTAMIDE &
NILUTAMIDE :
 synthetic, nonsteroidal antiandrogens

Dose : 250 mg tds, 50mg od resp.

MOA
 compete with the natural Hormone 
inhibits the translocation
AD:
GI upset, gynecomastia, liver toxicity
may occur (rare)
USES:
Palliative effect in metastatic Prostatic
Ca after orchidectomy
 Why flutamide given with
Goserelin and Leuprolide (GnRH
antagonist)?
 Testosterone to dihydro testosterone ( by 5œR)
 It is an analogue of androgen steroid hormones
like testosterone & DHT
 Orally active, high plasma protein bound, cross
BBB
 Metabolised in the liver by CYP3A4
(hydroxylation) *
 Elimination via feces and urine
 AD: sexual dysfunction, gynecomastia , CNS
toxicity – depression, anxiety
Leuprolide & Goserelin
 synthetic peptide analogs of naturally occurring GnRH, LHRH
 More potent than nature hormones

MOA: Gonadotropin RH secreted from hypothalamus and stimulate the

pituitary gland to secrete gonadotropic RH: FSH and LH
 analogs of GnRH bind to GnRH receptor in the pituitary gland and
leads to desensitization  inhibitory effects  low level of GnRH
(androgen and estrogen)

USES: prostatic cancer, advanced breast cancer

 Leuprolide – sustained released ppn, s.c., depot i.m. inj (metastatic
carcinoma of the prostate)
 Goeserelin acetate – i.m.

Androgen level initially may higher but then fall to castration levels

AD: impotence, hot flashes, and tumor flare (lesser than estrogen rx)
NAFERELIN :
 nasal spray / SC inj
 ↓FSH & LH release from pituitary
 ↓ the release of estrogen & testosterone
 USE : Breast Ca, Prostatic Ca
 Megestrol acetate
 used in the treatment of metastatic hormone
responsive
 breast and endometrial neoplasms
 Orally effective agent
 Other agents are compared to it in clinical trials
 Replaced with AIs
 A/E: bleeding
 Goodman & Gillman, pharmacologic basis of
therapeutics, edition 12th, part VIII, chapter:
60,
 Lippincott’s illustrated reviews, edition 4th,
chap-39.
 Katzung Pharmacology