Term
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Definition
Mechanism:
1. INHIBITS RIBONUCLEOTIDE REDUCTASE
reduction of ribonucleotides to deoxyribonucleotides is a rate limiting step in DNA synthesis
hydroxyurea inhibits the enzyme ribonucleotide reductase (specifically binds to the hRRM2 subunit and scavenges the tyrosyl radical), thereby blocking formation of deoxyribonucleotides needed for DNA synthesis
2. DNA SYNTHESIS INHIBITED
3. CELL ARREST NEAR G1-2 INTERFACE
cell may enter apoptosis
4. INCREASES EXPRESSION OF FETAL HEMOGLOBIN
therapeutic for sickle cell disease
5. INCREASES SENSITIVITY TO IRRADIATION
commonly used in combination with irradiation therapy
cells in G1 phase are more sensitive to irradiation
pyrimidine biosynthesis and hydroxyurea mechanism:
1. ENHANCES ANTIMETABOLITE INCORPORATION
[image]
this scheme illustrates the production of pyrimidines
hydroxyurea inhibits the ribonucleotide reductase enzyme thus interfering with conversion of UMP to dUMP and CTP to dCTP
also note that less dCTP will promote incorporation of more cytarabine into DNA
2. ARREST IN LAST G1 OR EARLY S PHASE
cells may arrest in last G1 phase (this is the phase when much of the enzyme and deoxyribonucleotides are produced in preparation for S phase)
purine biosynthesis and hydroxyurea mechanism:
[image]
1. ENHANCES ANTIMETABOLITE INCORPORATION
ribonucleotide reductase is also needed for purine nucleotide production
hydroxyurea blocks converstion of GMP to dGMP and AMP to dAMP
hydroxyurea enhances effect of fludarabine and cladribine (more DNA incorporation)
2. ARREST IN LATE G1 OR EARLY S PHASE
Drug Resistance:
TARGET ENZYME MUTATION
the main mode of drug resistance is increased production of the hRRM2 subunit of the ribonucleotide reductase enzyme
Toxicity:
LEUKOPENIA
like many antineoplastic agents, main toxicity is bone marrow depression
MEGALOBLASTIC ANEMIA
increased MCV, increased RDW
characterized by presence of large immature RBCs (megaloblasts)
a common cause of megaloblastic anemia is vitamin B12 deficiency
THROMBOCYTOPENIA (THERAPEUTIC VALUE)
this drug is sometimes used to treat thrombocythemia (high platelet count)
Other Considerations:
80-100% oral bioavailability
40-80% in urine unchanged
crosses the BBB and is found in breast milk
hydroxyurea does undergo hepatic metabolism, but the pathways are not well characterized |
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Term
| Platinum complexes: cisplatin, carboplatin, and oxaliplatin |
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Definition
Mechanism:
serendipitous discorvery
1. CROSSLINKING (N7-N7), INTRASTRAND
these drugs can enter the cell by diffusion or through a copper transporter
the most common reaction of platinum complexes is with 2 adjacent N7 on guanines on the same strand (intra-strand crosslinking)
adjacent A-G crosslinking also occurs
interstrand crosslinking occurs with much less frequency (1-3%)
2. REPLICATION AND TRANSCRIPTION INTERFERENCE
drug-DNA adducts interfere with replication and transcription
3. APOPTOSIS
Drug Resistance:
1. INTRACELLULAR NUCLEOPHILES (GLUTATHIONE)
react with the activated form of platinum complex drugs
2. ENHANCED DNA REPAIR (NUCLEOTIDE EXCISION)
the intrastrand crosslinking can be repaired by nucleotide excision repair mechanism
3. COPPER EFFLUX TRANSPORTERS
nucleotide excision repair of cisplatin-DNA adduct:
1. INTRASTRAND CROSSLINK
a single platinum complex drug (cisplatin) forms 2 covalent bonds with 2 adjacent guanines (N7-drug-N7)
2. CUTS ON EACH SIDE OF ADDUCT
the adduct is recognized and 2 cuts are made in the phosphodiester bonds on each side of the adduct
3. NUCLEOTIDE EXCISION
nucleotides are removed
4. NUCLEOTIDE REPLACEMENT
nucleotides are replaced by action of DNA polymerase |
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Term
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Definition
toxicity:
NEPHROTOXICITY - DOSE LIMITING
a major concern of cisplatin use is nephrotoxicity
renal function (BUN and creatinine) must be monitored during cisplatin use
AMIFOSTINE (thiophosphate) is dephosphorylated (by phosphatases) to a free thiol compound that can react with and neutralize cisplatin
amifostine is thought to accumulate in renal tubules and be present at higher concentration in normal tissue compared to tumor site
OTOTOXICITY
manifested by tinnitus and higher frequency hearing loss and may be unilateral or bilateral
other considerations:
RAPID PLASMA DECLINE (> CREATININE CLEARANCE) OF PARENT COMPOUND
parent drug is rapidly hydrated in plasma
some cisplatin is eliminated by kidneys and exceeds creatinine clearance (creatinine eliminated by diffusion, cisplatin is actively eliminated)
PLASMA PLATINUM 90% PROTEIN BOUND
platinum (not parent compound) tighly binds plasma protein and tissues
PLATINUM REMAINS IN TISSUES
patient hydration state is immportant for nephrotoxicity prevention |
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Term
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Definition
toxicity:
PERIPHERAL NEUROPATHY DOSE LIMITING
neuropathy of extremities is major concern with this drug (can be triggered by cold)
other considerations:
PLASMA CONCENTRATION OF PARENT COMPOUND RAPIDLY DECLINES
like cisplatin, the parent drug has a short plasma t1/2 |
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Term
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Definition
toxicity:
LESS OTOTOXICITY, NEUROTOXICITY, AND NEPHROTOXICITY
conversion to reactive (cytotoxic) intermediate is much slower than cisplatin or oxaliplatin
MYELOSUPPRESSION DOSE LIMITING
toxicity profile different compared to cisplatin, instead of the major concern with carboplatin use is bone marrow suppression |
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Term
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Definition
tretinoin
arsenic trioxide |
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Term
| tretinoin: all trans retinoic acid |
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Definition
USED TO INDUCE ACUTE PROMYELOCYTIC LEUKEMIA (APL) REMISSION
APL is associated with DNA sequence translocation between chromosome 15 and 17 resulting in abnormal fusion of DNA sequences
this particular sequence fusion results in dysfunctional retinoic acid receptor and dysfunctional PML gene product
normally the retinoic acid receptor causes cell differentiation, but in APL the retinoic acid receptor weakly responds to endogenous retinoic acid resulting in blood cell dedifferentiation (APL)
exogenous source (tretinoin) helps to maximize retinoic acid receptor activation and thus blood cell differentiation (remission of APL)
it is important to know that APL is characterized by immature (dedifferentiated) myelogenous cells
mechanism:
1. ACTIVATION OF RETINOIC ACID RECEPTOR (RAR) CAUSES CELL DIFFERENTIATION
2. IN APL, RETINOIC ACID RECEPTOR DYSFUNCTIONAL (PML-RAR GENE FUSION)
3. ORAL DOSE OF TRETINOIN ACTIVATES RECEPTOR
4. CAUSES CELL DIFFERENTIATION (APL REMISSION) |
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Term
| PML-RAR gene fusion associated with APL (acute promyelocytic leukemia) |
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Definition
[image]
a reciprocal DNA translocation event resulting in fusion of sequences of the PML (promyelocytic leukemia, chromosome 15) and RAR (retinoic acid receptor, chromosome 17) genes is strongly associated with development of acute promyelocytic leukemia (APL)
normally (without the translocation event) PML gene functions to keep myeloid cell proliferation under control
the fusion event renders the PML gene dysfunctional
RAR normally promotes myeloid cell differentiation into mature myeloid cells
the gene fusion causes decrease in RAR activity |
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Term
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Definition
INDUCES APL REMISSION
arsenic trioxide is similar to tretinoin in that it causes differentiation of immature cells in APL
DIFFERENTIATION OF APL (IMMATURE, PRECURSOR) CELLS
OTHER MECHANISMS (APOPTOSIS, FREE RADICALS, ANGIOGENESIS INHIBITION)
WELL TOLERATED
better tolerated compared to other cancer drugs
LENGTHENING OF QT INTERVAL
abnormal Ca and K flux in myocardium explains abnormal EKG
DIFFERENTIATION SYNDROME |
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Term
| APL differentiation syndrome |
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Definition
ASSOCIATED WITH TRETINOIN AND ARSENIC TRIOXIDE
arsenic trioxide (and tretinoin) induce maturation of the immature cells
however, a side effect associated with these 2 drugs is differentiation syndrome
this syndrome is characterized by fever, pulmonary effusion, mental status change, and possibly accompanied by leukocytosis
the effect is attributed to sudden drug induced maturation of the APL cells |
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Term
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Definition
treatment of multiple myeloma (MM)
this disease is characterized by production of malignant plasma cells (antibody producing B lymphocytes)
mechanism:
1. ANTIPROLIFERATIVE EFFECT
2. BLOCKS ADHESION WITH STROMAL BONE MARROW CELLS
stromal is a general term for a connective tissue cell that resides in many different organs (including bone marrow) and may provide support for division and survival
these surrounding stromal cells are not innocent bystanders in the process of tumor development
the stromal cells are thought to promote tumor progression
3. INHIBITS ANGIOGENESIS
4. ENHANCES NATURAL KILLER PRODUCTION
anti-multiple myeloma mechanisms of thalidomide:
[image]
A. INHIBITION OF TUMOR CELLS DIVISION
B. ADHESION OF TUMOR CELLS WITH STROMAL CELLS INHIBITED
interaction with surrounding bone marrow stromal cells enhances survival and division of tumor cells
C. INHIBITION OF ANGIOGENESIS
tumor cells in the bone marrow depend on formation of new blood vessels (angiogenesis) to supply nutrients
D. ENHANCED NATURAL KILLER CELL PRODUCTION
natural killer cells can attack and destroy tumor cells
this drug increases number of NK cells through enhanced conversion of T cells to NK cells
toxicity:
PERIPHERAL SENSORY NEUROPATHY
SEVERE BIRTH DEFECTS |
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Term
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Definition
INTRAVENOUS ADMINISTRATION
DRUG ACCUMULATES IN SKIN AND TUMORS
LOCAL PHOTOACTIVATION
light is applied locally (standard endoscopic technigue for esophageal and endobronchial cancer)
called photodynamic therapy
FREE RADICAL GENERATION
photoactivation causes generation of free radicals (hydroxyl) and local tissue damage
LOCAL TISSUE (TUMOR DAMAGE) |
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Term
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Definition
USED FOR CARCINOMA OF ADRENAL CORTEX
mitotane selectively destroys adrenal cortex cells (normal and tumor) and alters metabolism of cortisol
ANOREXIA AND NAUSEA ARE VERY COMMON
ADRENAL STEROIDS REPLACEMENT NEEDED
expectedly, adrenal insufficiency is a concern with use of this drug |
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Term
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Definition
mechanism:
INHIBITS PROTEASOME PATHWAY
the proteasome pathway degrades proteins targeted by ubiquitination
in general, this is a mechanism by which the cell maintains homeostasis (regulates intracellular protein levels)
PROTEIN DEGRADATION BLOCKED (IKAPPAB)
concerning anticancer mechanism, regulation of IkappaB concentration in cell cytosol is important
IkappaB is bound to NK-kappaB in the cytosol, thus preventing NF-kappaB from entering the nucleus
IkappaB is ubiquitinated and then degraded by 26S proteasome complex causing increased free NF-kappaB which can then enter the nucleus and activate gene transcription
GENE TRANSCRIPTION INHIBITED (CELL SURVIVAL GENES)
cell cannot produce proteins that promote cell survival such as adhesion molecules and growth factors in presence of bortezomib
adverse effects:
THROMBOCYTOPENIA
GI |
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Term
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Definition
INHIBITS HISTONE DEACETYLASES
INCREASES LYSINE ACETYLATION
ACTIVATES GENE TRANSCRIPTION
[image]
some cancers are associated with increased expression of histone deacetylases, enzymes that remove acetyl group from lysine of histones and other proteins (transcription factors) which results in hypoacetylation of histones, condensed chromatin structure, and repression of gene transcription
histone deacetylase inhibitors cause more acetylation of lysine residues on histones which is thought to favor transcription of genes that regulate cell division, cause cell differentiation, and apoptosis |
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Term
| hormones and antagonists used as chemotherapy |
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Definition
the effectiveness of these drugs is found on the idea that certain neoplastic diseases (breast or prostate cancer) depend on presence of sex hormones (estrogens and androgens) for cell division and survival
SERMs have tissue dependent estrogen activity (have agonist activity on one tissue type, but antagonist activity on another)
anti-estrogen implies pure antagonist activity (has antagonist activity on all tissues |
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Term
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Definition
TUMOR SUPPRESSOR GENE MUTATIONS (RB1, P53, BRACA)
certain hereditary mutations in tumore suppressor genes correlate with development of breast cancer (BRCA1, breast cancer 1 and BRCA2, breast cancer 2)
other mutations are aquired by the tumor cells during transformation or progression such as RB1 and p53
ASSESSMENT OF ESTROGEN RECEPTOR (ER) AND HER-2
breast cancer prognosis and treatment options can depend on the presence of oncogene HER-2 (human epidermal growth factor receptor-2)
the estrogen receptor (ER) is assayed in tumor biopsies
expression of ER by breast cancer cells correlates with responsiveness to anti-estrogen therapy |
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Term
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Definition
MUTATIONS IN TUMOR SUPPRESSOR GENES (P27, PTEN)
loss of certain tumor suppressor genes are associated with this disease (p27 regulates cell cycle; PTEN encodes a phosphatase that controls cell cycle)
PSA is useful in the assessment of prostate cancer
serum PSA is elevated in BPH and in malignant cancer
prostate cancer is associated with higher serum levels; however when used for prostate cancer detection, PSA test may result in false negative or false positive
other causes of elevated serum PSA are inflammation and infection
PSA is thought to be important for egg fertilization |
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Term
| the hypothalamic pituitary reproduction axis |
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Definition
[image]
1. PULSATILE GNRH RELEASE
2. LH AND FSH PRODUCTION AND RELEASE
3. STIMULATION OF OVARIES OR TESTES
4. NEGATIVE FEEDBACK CONTROL |
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Term
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Definition
[image]
2 major therapeutic mechanisms are receptor antagonism and inhibition of hormone release
finasteride: inhibits 5 alpha reductase, the enzyme that converts testosterone to DHT (dihydrotestosterone)
aromatase is the enzyme that converts testosterone and androstenedione to estrogens (estradiol and estrone respectively); there are several drugs that inhibit the action of aromatase
SERMS (selective estrogen receptor modulators): antagonize the effect of estrogens (-) or have estrogen like activity (+) depending on the drug and target tissue
androgen receptor antagonists: block the activity of dihydrotestosterone (and testosterone)
in addition to aldosterone inhibition, spironolactone has anti-androgen activity |
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Term
| production of estrogen in ovaries involves 2 cell types |
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Definition
[image]
LH promotes androgen synthesis in thecal cells
androgen then diffuses into nearby granulosa cells
the androgen can be converted to testosterone or estrone
testosterone can be converted to estradiol
aromatase catalyzes conversion of androgens to estrogens
FSH increases aromatase activity in granulosa cells, promoting the conversion of androgen to estrogen |
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Term
| anti-androgens: biclutamide, flutamide, nilutamide |
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Definition
prostate cancer treatment
mechanism:
TUMOR GROWTH ANDROGEN DEPENDENT
these drugs are non-steroidal androgen antagonists
growth of metastatic sites that originated from primary tumor usually retain dependency on androgens
BLOCKS ENDOGENOUS ANDROGEN BINDING TO RECEPTOR
INHIBITS NUCLEAR TRANSLOCATION
therefore, the receptor cannot regulate gene transcription
COUNTERACTED BY INCREASED LH
when these drugs are used alone their effects are counteracted by an increase in LH
blocking the action of androgens on prostate also blocks the negative feedback causing a rise in LH to promote the production of testosterone
the effects of androgens are mediated through a receptor that regulates DNA transcription
the receptor has an androgen (hormone) binding domain, a DNA binding domain, and other regulatory domains
1. ENDOGENOUS ANDROGEN BINDS RECEPTOR IN CYTOSOL (BLOCKED BY DRUG)
2. RECEPTOR-ANDROGEN COMPLEX ENTERS NUCLEUS
the receptor must bind androgen before entry into the nucleus
b/c drug inhibits this interaction, nuclear entry is blocked
3. COMPLEX REGULATES DNA TRANSCRIPTION
in presence of drug, testosterone cannot have effect on gene transcription
use:
COMBINED WITH GNRH AGONISTS (ANALOGS) FOR PROSTATE CANCER
the anti-androgens also block the negative feedback to hypothalmus and anterior pituitary, so the result is increased secretion of LH and FSH, and stimulation of testosterone production in the testes
the lack of negative feedback lessens the effectiveness of these drugs
continuous administration of GnRH analogs suppress the production and release of LH and FSH from the pituitary
unwanted effects:
HOT FLASHES, GYNECOMASTIA, IMPOTENCE, RARE HEPATIC INJURY
due to lack of androgen receptor activation
liver transaminases should be monitored |
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Term
| action of testosterone and mechanism of finasteride |
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Definition
1. TESTOSTERONE DIFFUSION
2. RECEPTOR BINDING
3. NUCLEAR ENTRY OF COMPLEX
4. REGULATION OF GENE TRASCRIPTION
finasteride use: BPH, alopecia, prostate cancer (off label)
in some tissues (prostate, live, skin) testosterone is converted to DHT by 5 alpha reductase
DHT has higher affinity for the androgen receptor compared to testosterone
the enzyme is inhibited by the drug finasteride which is used to treat benign prostatic hypertrophy and alopecia in men |
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Term
| SERMs (tamoxifen, toremifene) and anti-estrogens (fulvestrant) |
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Definition
TISSUES SUBJECT TO ESTROGEN EFFECT: bone, endometrium, breast
THERAPEUTIC MECHANISM IN BREAST CANCER:
1. BREAST CANCER CELLS MAY BE DEPENDENT ON ESTROGENS (ESTRONE, ESTRADIOL) FOR GROWTH
2. SERM BINDING TO ER MAY ACT AS AGONIST OR ANTAGONIST (TISSUE DEPENDENT)
3. FULVESTRANT DECREASES ER EXPRESSION
estrogen helps maintain bone density (rationale behind estrogen replacement therapy in postmenopausal women)
estrogen promotes growth of endometrial tissue
in breast cancer, estrogen may promote growth of tumor cells
SERMs block the effect of estrogens on tumor growth
TAMOXIFEN:
tamoxifen is not a pure estrogen antagonist (more properly called a SERM)
in some tissues tamoxifen has same effect as estrogen (but lower potency)
in other tissues tamoxifen antagonizes the effect of estrogen
in breast tissue, especially some tumor cells, tamoxifen inhibits growth (acts as an antagonist)
tamoxifen stimulates endometrial growth and has a positive effect on bone density
the effect on bone density is considered a good effect of tamoxifen
TOREMIFENE
another SERM with similar pharmacological profile as tamoxifen
FULVESTRANT
no estrogen activity (antagonist) - is a pure estrogen antagonist
additionally decreases ER expression (also called a SERD, selective estrogen receptor down regulator) |
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Term
| effects of anti-estrogens/SERMs on breast cancer cells |
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Definition
[image]
1. anti-estrogens (AE) or SERMs bind the estrogen receptor (ER) in the tumor cell nucleus (block binding of endogenous estrogens)
2. Drug-ER complex alters gene transcription through interaction with the estrogen response element (ERE) on DNA
3. insulin-like growth factor (IGF-1) receptor decreased (less effect from IGF-1 released from nearby stromal cells)
decreased production of transforming growth factor (TGF)-alpha by the tumor cell
increased production of TGF-beta by the tumor cell
4. IGF-1 and TGF-alpha have stimulatory effect on tumor cell growth and TGF-beta has an inhibitory effect on tumor cell growth
5. the end result is decreased division of the breast cancer cell |
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Term
| partial effect (partial agonist) activity of tamoxifen |
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Definition
[image]
estrogen: X and Y coactivators recruited -> 3 genes expressed
SERM (tamoxifen): only X coactivator recruited -> 1 gene expressed |
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Term
| concerns associated with tamoxifen and tremifene |
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Definition
INCREASED RISK OF ENDOMETRIAL CANCER AND UTERINE SARCOMA
due to the estrogen like effects of tamoxifen
INCREASED RISK OF THROMBOEMBOLISM (ANTI-THROMBIN III DECREASE)
increased thrombotic events particularly thromboembolism (correlated with decreased anti-thrombin III factor which is a natural endogenous inhibitor of thrombin coagulation factor)
HEPATIC CANCER IN ANIMALS
no risk was found in human studies |
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Term
| gonadotropin releasing hormone analogs (histreline, leuprolide, goserelin, triptorelin) |
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Definition
used for hormone dependent cancers
mechanism:
1. NONAPEPTIDE OR DECAPEPTIDE
2. CONTINUOUS (IMPLANTS AND MICROSPHERE INJECTION) ADMINISTRATION CAUSES SUSTAINED DECREASE OF LH AND FSH
the initial effect is surge in LH and FSH production by the anterior pituitary gland, then levels rapily decline resulting in depressed estrogen and androgen production from ovaries and testes
3. RESULTS IN DECREASED ESTROGENS AND ANDROGENS
continuous administration of GnRH analogs suppress LH and FSH release from the anterior pituitary gland, thus preventing gonadal hormone synthesis
leuprolide depot effect on serum testosterone:
[image]
immediately following the first injection there is a spike in serum testosterone (b/c of rapid rise in LH)
testosterone falls b/c LH secretion is inhibited by sustained leuprolide release from depot
testosterone levels remain suppressed
suppression is reversible |
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Term
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Definition
type 1 inhibitor (steroidal) = exemestane
type 2 inhibitors (nonsteroidal) = anastrozole and letrozole
mechanism:
1. BLOCK ANDROGEN CONVERSION TO ESTROGENS
aromatase is produced by granulosa cells in the ovaries and other peripheral tissues including fat cells, liver, brain, normal and cancerous cells in the breast
2. PRESENT IN BREAST TUMORS
3. INHIBITS ESTROGEN DEPENDENT TUMOR GROWTH
anastrozole and letrozole:
reversible enzyme inhibition
exemestane:
irreversible inhibition
earlier generation aromatase inhibitors are not specific for inhibition of estrogen synthesis (also block adrenal steroid production)
anastrozole and letrozole have little effect on production of other hormones (unlike first and second generation aromatase inhibitors) |
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Term
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Definition
aromatase is a member of the cytochrome P450 family of enzymes
the drug inhibitors are not 100% specific for aromatase
these drugs do have some inhibitory activity on other P450 family members which results in metabolic drug interactions |
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Term
| aromatase inhibitors: concerns |
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Definition
BONE RESORPTION
b/c of low estrogen levles
EFFECT ON SERUM LIPID PROFILE
letrozole increases total and LDL cholesterol |
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