Transcript Estrogen receptor modulators and down regulators

Estrogen Receptor Modulators
And Down Regulators
Presented by :Eman Youssif
Supervised by: Prof. Nashaat Lotfy
Professor of Oncology
Faculty of Medicine
The goal of anti-estrogen therapy:
• Ati-estrogen therapy is to prevent estrogen
from helping cancer cells grow. This may be
done in several ways including blocking
estrogen function through drugs.
• Other ways include stop estrogen production
or interrupt it's synthesis
Who can benefit hormonal therapy?
test for estrogen and
progesterone receptors
is important
Hormone sensitivity
Estrogen is feeding
certain types of cancer
cells
Tissue staining
Estrogen
receptor
positive (ER+)
Response
Resistance,
even after
initial response
Estrogen
receptor
negative ( ER-)
Hormone
therapy is not
useful
Classification of
the different
compounds
Tamoxifen
Selective estrogen
receptor
modulators(SERMs)
Raloxifen
Ant estrogenic
therapy
Selective estrogen
receptor down
regulators(SERDs)
Fluvestrant
Selective estrogen receptor
modulators (SERMs):
• During the 1980s tamoxifen became the first
anti-estrogenic therapy targeted to the ER for
adjuvant therapy.
• Tamoxifen like drugs are developped (through
changes In the chemical structure)in order to
improve the efficacy and reduce the toxicity of
tamoxifen (toremifene, droloxifene, idoxifene).
• Changing the tamoxifen chemical structure in to a
fixed ring strucure resulted in a fixed ring
structure (raloxifene and arzoxifene).
Selective estrogen
receptor modulators
(SERMs):
The action of the SERMs tamoxifen
and raloxifene at target sites around a
postmenopausal woman’s body.The
SERMs switch on (estrogenic action) or
switch off (antiestrogenic action) at
different target sites.
The decision network that a
SERMmust navigate to switch on or
switch off an estrogenic response at a
target site.1, a SERMhas the
opportunity to interact either with
membrane-bound ER as part of the
cell surface receptor signal
transduction phosphorylation cascade
or with the nuclear ERs.The shape of
the SERMis important to create
optimal antiestrogenic folding of the
ER complex. 2, there are two ERs (ER-α
and ER-β) that can produce opposing
biological actions based on the shape
(3) or the phosphorylation (4) state of
the SERMER complex. There will be an
interaction with either a coactivator
protein to induce a response or a
corepressor protein to block a
response (3). Additionally, based on
shape, there may be destruction (5) of
the SERMER complex by the
proteosomes or accumulation. Finally,
the SERMER complex may activate (6)
the promoter region of genes directly
at the DNA (genomic) or via activator
protein (AP-1) sites with a protein
protein interaction (tethered). The
Biology Behind
SERMs
tamoxifen:
Indications:
• Adjuvant therapy in brest cancer.
• Metastatic Breast Cancer.
• Reduction in the Incidence of Breast Cancer in Women
at High Risk.
• Male Breast Cancer
Dose:
• 20 mg daily. Administered orally.
SERMs
tamoxifen:
Drug interactions:
• Tamoxifen should not be administered with
anastrozole. Concurrent use decreased anastrozole
plasma levels by 27%.The combination had no efficacy
benefit when compared to tamoxifen administration
alone. Tamoxifen pharmacokinetics were not affected.
• Tamoxifen enhance anticoagulant effect of coumarins.
• Strong inhibitors of CYP P-450-2D6 may inhibit the
metabolism of tamoxifen to endoxifen (an active
metabolite of tamoxifen). fluoxetine, paroxetine,
quinidine, chlorpromazine, quinine and, terbinafine,
are expected to have similar effects.
Tamoxifen is broken down by 2D6 enzymes into a chemical called
endoxifen. Endoxifen is the active agent that helps prevent
hormone-positive breast cancer from recurring. It is 100 times
more potent than tamoxifen itself.
Normal Tamoxifen Metabolism
Tamoxifen-Paxil Traffic Jam
SERMs
tamoxifen:
Lactation:
Absolute Contraindication
Pregnancy:
Not Recommended
Pediatric:
Relative Contraindication: safety and efficacy
not established.
SERMs
tamoxifen:
Cautions:
• Occasional cystic ovarian swlling in
premenopausal women.
• Increased risk of thromboembolic events
when used with cytotoxics.
• Endometrial changes(hyperplasia, polyps,
cancer, uterine sarcoma)
SERMs
tamoxifen:
Adverse Effects:
Dry Skin, Genital Organ Pruritus, Headache
Disorder, Irregular Menstrual Periods, Nausea,
Skin Rash, Vaginal Discharge, Vasomotor
Symptoms associated with Menopause,
Vomiting, Weight Gain, risk for
thromboembolism.
SERMs
Raloxifene:
Inndications : (in oncology)
• Prevention of breast carcinoma.
Dose:
• 1 tablet (60 mg) by oral route once daily.
Drug interactions:
• Cholestyramine was found to decrease the absorption
and enterohepatic circulation of raloxifene by 60%
after only one dose. Other anion exchange resins, such
as colestipol, are thought to produce similar effects.
• The drug may be taken without regard to meals or time
of day. Raloxifene may be administered concomitantly
with calcium carbonate or aluminum and magnesium
hydroxide-containing antacids.
SERMs
Raloxifene:
• Although plasma concentration is higher in
patients with renal and hepatic impairement ,
The manufacturer makes no specific
recommendations for raloxifene dosage
adjustment .
• However, the drug is extensively metabolized
in the liver and excreted principally in feces.
SERMs
Raloxifene:
Lactation :
Absolute Contraindication.
Pregnancy :
Absolute Contraindication.
Adverse Effects :
Chest Pain, Cramps in Legs, Cystitis, Fever, FluLike Symptoms, Infection, Peripheral Edema,
Pharyngitis, Sinusitis, Skin Rash, Urinary Tract
Infections, Vaginitis, Vasomotor Symptoms
associated with Menopause
Resistance to SERMs:
• Early or late tamoxifen treatment may result in
resistance .
• Tamoxifen-resistant breast cancers can remain
estrogen dependant and respond to a second line
endocrine therapy.
• In some cases after prolonged tamoxifen use, not
only resistance develop, but also breast cancer
seem to be stimulated by it . some of these
tumors regress after withdrawal.
• All SERMs show high level of cross resistance with
tamoxifen.
New biomarker predicts
effectiveness of breast cancer
drugs:
• Since evidence shows anti-esrogen drugs will
fail in many patients with ER+ breast cancer, it
better to examine both ER status and
retinoblastoma (RB) tumor suppressor status
during the initial diagnosis, in order to
prescribe the most effective therapy for that
specific patient's cancer.
Selective estrogen receptor
down regulators (SERDs):
• SERDs (e.g. fluvestrant), like endogenous
estradiol, they have a steroid structure, and
like a SERM, they bind to an ER.
• SERDs competitively inhibit estrogen binding
and induce a rapid, proteosome dependant
degradation of the receptor
• Fluvestrant has a much higher ER-binding
affinity than tamoxifen.
Selective estrogen receptor
down regulators (SERDs):
• Fluvestrant neither increases endometrial thickness nor
expected to increase endometrial cancer incidence because
it's a pure anti-estrogen and lacks a tissue or receptor
dependant estrogenic effect.
• Its clinical utility is limited by its poor bioavailability and the
length of time it takes to achieve a useful therapeutic
concentration in target tissues. Half-life Approximately 40
days.
• New SERDs are being tested, they show better oral
bioavailability.(some will be used SC).
SERDs
fluvastrant
Indications:
• Treatment of ER+ metastatic or locally
advanced breast cancer in postmenopausal
women in whom disease progress or relapses
while on or after another anti-estrogen
therapy.
Dose:
• By deep IM injection,250mg muscle/4 weeks
in to mgluteal muscle.
SERDs
fluvastrant
Disease Contraindications:
• Blood Coagulation Disorder.
• Lactating Mother.
• Pregnancy.
• Thrombocytopenic Disorder.
SERMs - Prof.S.N.Panda - 45th. AICOG
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