drugs for breast and prostatic cancer, corticostroids in hormone dependent cancers

1. Chemotherapy Of Cancer
Hormones & Antagonists
By
Dr. Harshika Patel
KeMU
Basic Pharmacology and Toxicology

3. Drugs altering hormonal milieu
1. Glucocorticoids: Prednisolone and others
2. Estrogens: Fosfestrol, Ethinyl-estradiol
3. Selective estrogen receptor modulators:
Tamoxifen, Toremifene
4. Selective estrogen receptor down regulator:
Fulvestrant
5. Aromatase inhibitors: Letrozole, Anastrozole,
Exemestane
6. Antiandrogen: Flutamide, Bicalutamide
7. 5-α reductase inhibitors: Finasteride,
Dutasteride
8. GnRH analogues: Naferelin, Triptorelin
9. Progestins Hydroxyprogesterone caproate, etc.

4. Introduction
•Growth of a number of cancer tumor either
dependent or regulated by hormones.
Particularly,
•Molecules work by:
oInterrupt the stimulate axis  created by 
systemic pool of androgens and estrogens
oBy inhibiting hormone production, or
oBy binding to receptors,  ultimately, block the
complex expression of genes that promotes tumor
growth and survival
Sex hormones and adrenocortical hormones

5. • sex hormone therapy or ablation of appropriate endocrine
organs  Proven to be effective in extending survival , delaying
or preventing tumor recurrence (B/P cancers)
• The mechanisms of action: have been partially clarified ( B/P/
lymphoid cancers):
oSpecific cell surface receptors have been identified for
estrogen, progesterone, corticosteroids, and androgens in
neoplastic cells in these tissues*
osteroid-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?  molecular testing

7. General uses of sex hormones
•Breast, prostate and endometrium cancers
oWith replacement doses: estrogens stimulate the
breast and endometrial cancer
oBut at higher doses can suppress the tumor mass
(metastatic breast cancer )
oLargely replaced by antiestrogen agents
•Prostate cancer:
oAndrogen stimulate the growth while estrogen
reduce the androgen level.
oDrugs which reduce the production of androgen or
block the effect of that hormones at receptor level are
also effective in prostate cancer.

8. Corticosteroids
Prednisone to/ Prednisolone :
•Curative regimens for other lymphoid
malignancies: like
Hodgkin's, non-Hodgkin's lymphoma, multiple myeloma,
chronic lymphocytic leukemia (CLL), acute leukemia in
children
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

9. 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 a sense of well being
– Increase body weight
– Suppress hypersensitivity reaction
– Control hypercalcemia & bleeding
– Non-specific antipyretic effect
– Increase the antiemetic effect of ondansetron
• extremely helpful in controlling auto-immune hemolytic anemia and
thrombocytopenia associated with CLL
In liver abnormality 
prednisolone is
prescribed not
prednisone

10. Adverse effects: ulcer and pancreatitis
•Rarely occurred : hyperglycemia, cataract
formation, glaucoma, osteoporosis, and
change in mood (euphoria or psychosis)
•Dexamethasone, are used in conjunction
with radiotherapy to reduce edema
related to tumors

11. Estrogen – Ethinyl Estradiol
• Physiological antagonists of androgens  Thus used to
antagonize the effects of androgens in androgen dependent
prostatic cancer
• Largely replaced by the GnRH analogs because of fewer adverse
effects
• 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 experienced gynecomastia and
impotence

12. •Fosfestrol
– Prodrug , phosphate derivative of diethyl
stilbesterol used to treat prostate cancer
– 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

13. Progestins
•Hydroxyprogesterone
•Medroxyprogesterone
•Poorly absorbed when given orally so
given by IM
•Second-line hormonal therapy for metastatic
hormone-dependent breast cancer
•Management of endometrial carcinoma
previously treated by surgery and
radiotherapy

14. -Structurally related to
synthetic estrogen,
diethylstilbesterol
-Has weak estrogenic
activity  10 fold
lower affinity to ER
than estradiol
Fails to induce estrogen-responsive gene
Hence RNA synthesis doesn’t arise

15. •Result is a depletion (down-regulation) of estrogen
receptors
•Supressed the:
• Growth-promoting effects of the natural hormone
• Other growth factors: in serum insulin-like growth factor-
1 and up-regulates local production of transforming growth
factor-beta
•In premenopausal women the drugs prescribed with
GnRH analog (leuprolide)  decrease the estrogen
level
•Tamoxifen is not affected any phase of cell cycle
Resistance :
Decreased affinity for the receptor or the presence of
a dysfunctional receptor.

16. DOSE:10-20mg bd, high dose can cause retinal
degeneration (~200mg/day)
• 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 and absorbed well in body, has higher
plasma half life than estradiol (7-14 days)
• Metabolised in liver by CYP3A4 and 5 and 2D6 some
metabolised have antagonised actions and some have
agonist activity, predominately excreted thr’ bile in the
feces
•Dose adjustment is required in ….?

17. Adverse effects:
•Hot flushes
•Vomiting
•vaginal bleeding
•menstrual irregularities
•venous thromboembolism
•Dermatitis
•rarely endometrial cancer

18. Toremifene
• 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 agent
• Plasma protein bound mainly albumin (~92%)
• Hepatic activation by enz CYP3A4 N-demethyltoremifene,
which also has antiestrogenic action but with weak in vivo
antitumor potency
• Excreted via bile in feces
Why in post
menopause???

19. Selective Estrogen Receptor Down regulator
(fulvestrant)
• 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

20. 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

21. Aromatase Inhibitors
“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 initial therapy or after tamoxifen
•First generation AIs:
Aminoglutethimide
•Second generation:
Formestane, Exemestane
•Third gereration:
Anastrozole , Letrozole
Synergism

22. Aminoglutethimide
•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

23. 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 :
• 1mg OD in ER+ Breast Ca
• A/E : hot flushes
• Second line drugs for hormone
dependent BC after temoxifen
in U.S. in other country first line
drug for postmenopause BC
• Liver metabolism occurred

24. Exemestane
•A steroidal, irreversible inhibitor of
aromatase,
•Orally well absorbed and widely
distributed. Hepatic metabolism is by the
CYP3A4 isoenzyme,
•Because of 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.

25. Exercise
•What is triple negative breast
cancer (TNBC)?
•Discuss the treatment options of
the same?

26. Chemo drugs for BC and advance BC
• https://www.cancer.org/cancer/breast-
cancer/treatment/chemotherapy-for-breast-cancer.html
• https://www.cancer.org/cancer/breast-
cancer/treatment/hormone-therapy-for-breast-
cancer.html --> hormonal drugs for BC
• https://www.cancer.org/cancer/prostate-
cancer/treating.html all in one about prostate cancer
AMERICAN CANCER
SOCIETY

27. Anti androgens
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

28. Why flutamide given with
Goserelin and Leuprolide (GnRH
antagonist)?

29. 5œ - reductase inhibitors
Finasteride/Dutasteride
•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
•USES: BPH, androgenic alopecia
•AD: sexual dysfunction, gynecomastia , CNS toxicity
– depression, anxiety

30. GnRH agonists: Leuprolide & Goserelin
• Synthetic peptide analogs of naturally occurring GnRH, LHRH
• More potent than natural 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)
• Goserelin acetate – i.m.
Androgen level initially may higher but then fall to castration
levels
ADR: impotence, hot flashes, and tumor flare (lesser than
estrogen rx)

31. NAFERELIN :
•Nasal spray / SC inj
•↓FSH & LH release from pituitary
•↓ the release of estrogen &
testosterone
•USE : Breast Ca, Prostatic Ca

32. PROGESTINS:
•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

33. References
•Goodman & Gillman, pharmacologic basis
of therapeutics, edition 12th, part VIII,
chapter: 60,
•Lippincott’s illustrated reviews, edition
4th, chap-39.
•Katzung Pharmacology
•Internet sources

34. THANK YOU
?