Medical Pharmacology Chapter 33-34: Anticancer Drugs
Hormonal Anticancer Drugs:
A number of different classes of hormonal agents may be used in cancer therapeutics or in chemoprevention.3,1
such as: Tamoxifen 5, Nolvadex, Soltamox)
Tamoxifen acts by binding competitively at estrogen receptors on tumors as well as other tissue targets.
This agent is classified as a "selective estrogen receptor modulator (SERM).
Tamoxifen-estrogen receptor binding inhibits translocation as well as nuclear binding of the estrogen receptor.3
As a result, both transcriptional and post-transcriptional activities influenced by this receptor are changed.3
Tamoxifen administration results in cell concentration in the G0 and G1 phases, suggesting that tamoxifen is not cytocidal but rather cytostatic.5
Selective estrogen receptor modulators (SERMs), such as tamoxifen, upon binding to the estrogen receptor can promote estrogenic or antiestrogenic effects, depending on the target organ.1
Tamoxifen is considered the most widely examined antiestrogenic drug employed in breast cancer treatment.1
However, tamoxifen does exhibit estrogenic, agonist activity on non-breast tissue.
Newer, novel antiestrogen drugs have been developed that promise both improved efficacy with reduced toxicity relative to tamoxifen.
These antiestrogens have been classified as either tamoxifen analogs (e.g. toremifene (Fareson); "fixed-ring" agents (e.g. raloxifene (Evista), lasofoxifene (Fablyn) or agents that are pure antiestrogens (SERD, Selective Estrogen Receptor Degrader, an example of which is fulvestrant (Faslodex).1
Following oral administration, tamoxifen is easily absorbed.
Peak plasma levels are obtained in about 5 hours.1
Steady-state tamoxifen concentrations may be demonstrated in about weeks.
Metabolism involves mainly the cytochrome P450 drug metabolizing system, more particular certain isoforms, namely CYP3A4 and CYP3A5 along with CYP2D6.1
Cytochrome P450 enzymes promote formation of N-desmethyl tamoxifen (CYP3A4 and CYP3A5); whereas, formation of the metabolite 4-hydroxytamoxifen is catalyzed mainly by CYP2D6.
These two metabolites may be further transformed to another active metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen).1,9
Tamoxifen metabolism involves enterohepatic circulation1
Enterohepatic circulation describes primarily biliary acid, bilirubin, and drug circulation from the liver to the bile with subsequent entry into the small intestine, followed by enterocyte absorption and subsequent transport back to the liver.
Following enterohepatic circulation glucuronides (phase II metabolism) and other metabolites or excreted in the feces.
Limited urinary excretion is noted. CYP2D6 polymorphisms which reduces enzymic activity has been considered as a clinical issue since such polymorphisms might reduce plasma levels of important, therapeutically active metabolites (e.g. endoxifen and 4-hydroxy tamoxifen).
At this time (2016) this polymorphism has not been clearly linked to decreased tamoxifen treatment efficacy.1,10
Similarly, some drugs that inhibit CYP2D6 were evaluated as possibly reducing tamoxifen efficacy in breast cancer; however, relatively recent studies (2016) have not demonstrated a clinical impact.1,10
Tamoxifen administration results in both beneficial and harmful side effects.3
An example of a beneficial effect associated with tamoxifen administration is a reduction in total cholesterol and retention of bone densities in postmenopausal patients.
By contrast, in premenopausal women tamoxifen reduces bone density.
The most frequently observed side effect due to tamoxifen administration is hot flashes which occurs in about 50% of treated individuals.3
Varying intensities and hot flash duration tend to stabilize following the first three months of therapy.
Although high-dose estrogen is effective in treating breast cancer, side effects, particularly thromboembolism resulted in development of other drugs.
An agent initially developed for use in oral contraception, tamoxifen, exhibited anticancer efficacy and metastatic breast cancer in the 1970s, several years after its initial synthesis in 1966.2
Tamoxifen represents a prototypic drug used in treating estrogen receptor positive (ER+) (expressed, ER+) breast cancer.
Tamoxifen is not only used in prevention but also in treatment of various disease stages, prominently in early-stage breast cancer as well as an advanced disease.2,1
With respect FDA approval, tamoxifen uses include:3
Premenopausal breast cancer prevention
Treatment of ductal carcinoma in situ (DCIS)
Adjuvant treatment in surgically removed premenopausal estrogen receptor positive (ER+) breast cancer
Treatment of metastatic ER+ breast cancer
Toremifene is a triphenylethylene, nonsteroidal derivative of tamoxifen,with a chlorine substitution at the R2 position1.
Toremifene binds to estrogen receptors on tumors and as a consequence, limits estrogen-mediated growth stimulation.
Since toremifene exhibits cross-resistance with tamoxifen, toremifene would not be expected to be effective in tamoxifen-resistant cancer.
Toremifene is well absorbed and exhibits a volume of distribution (Vd) of about 600 L.
This agent exhibits substantial plasma protein binding, mainly to albumin (binding: >99.5%).
This drug is substantially metabolized by the liver, principally by the cytochrome P450 isozyme (isoform) CYP3A4.
Principal P450 metabolites are N-demethyltoremifene and 4-hydroxytoremifene.
Drug bioavailability is not influenced by food with the drug elimination half-life for toremifene being about six days.
This agent is excreted primarily in the feces.
Toremifene side effects are generally similar to those observed with tamoxifen.
represent the most common side effect.
Raloxifene is a related compound, a polyhydroxylated nonsteroidal agent, characterized by a benzothiophene core. This agent exhibits high affinity binding for estrogen receptors (ERα and ERß)1
Raloxifene is described as exhibiting both estrogen agonist and antagonist properties i.e. a selective estrogen receptor modulator (SERM).14
Accordingly, some estrogenic pathways are activated while others are blocked by this drug. For example, raloxifene prevents bone loss through agonist activity while inhibiting some estrogen effects in breast and uterine tissue (antagonist).
Raloxifene reduces bone resorption thereby strengthening bone by increasing mineral density and, as a result, reducing the likelihood of fracture.14
Raloxifene is rapidly absorbed.
Absorption is about 60%.
This agent exhibits a high volume of distribution (>2000 L/kg).
Raloxifene exhibits significant protein binding mainly to albumin and α-glycoprotein).
Raloxifene is metabolized by the liver with substantial first-pass metabolism.
Raloxifene is metabolized to glucuronide conjugates (phase II metabolism).
Raloxifene half-life of elimination, following a single dosage is about one day.
Excretion is primarily in the feces and secondarily in the urine.14
Raloxifine is contraindicated in pregnancy and in patients exhibiting a history that includes thromboembolic pathologies, such as DVT or retinal vein thrombosis).
Thromboembolic events represent a primary, serious adverse effect.
Deep vein thrombosis and pulmonary embolism risk is reported as higher during the initial four months of treatment.
Cardiovascular disease risk is elevated in certain patient subgroups. For example risk of death (from stroke) is elevated in postmenopausal women with coronary heart disease.
Increased risk applies also to "coronary events."
use is recommended in those patients exhibiting liver function
impairment and/or renal impairment.14
Pure Antiestrogens ("Selective Estrogen Receptor Downregulators")
Overview: The pure antiestrogens also referred to as SERDS or Selective Estrogen Receptor Downregulators do not exhibit any estrogen agonist property.
Presently, January 2020, fulvestrant (Faslodex) is the only FDA-approved SERD.
Fulvestrant is a 7 α-alkylamide analog of 17 ß-estradiol.2
The designation, SERD, (selective estrogen receptor down-regulator) is appropriate since the agent decreases cellular estrogen receptor protein levels.2
Fulvestrant may be administered as monotherapy or in combination with palbociclib (a CDK4/6 inhibitor).1
CDK is an abbreviation for cyclin -dependent kinase.15
Therefore, a CDK4 inhibitor blocks CDK function.
Ibrance (palbociclib) is the first FDA-approved drug in this classification (February, 2015) with an indication of use in postmenopausal women whose breast cancer is both estrogen receptor positive and HER2 negative.
Cyclin-dependent kinase enzyme, when inhibited, stops or delays cell-cycle progression.16
Cell cycle arrest is likely to occur at the G1 phase.
Cyclin-dependent kinase inhibitors are often proteins.
Following IM (intramuscular) administration, fulvestrant steady-state levels are obtained in about one month (additional dose administered two weeks following first dose).
Oral absorption of fulvestrant has not been found reliable.2
Therefore, this agent is administered by a monthly depot intramuscular route of administration.2
Volume of distribution (Vd) is roughly 4 L/kg.
Fulvestrant binds prominently to plasma proteins, 99%, particularly to VLDL, LDL and HDL lipoprotein components.
Fulvestrant is metabolized utilizing the cytochrome P450 hepatic microsomal drug metabolizing system.
The cytochrome P450 isoform CYP3A4 may be the primary isoform involved.1
Fulvestrant exhibit several biotransformation pathways including those involving oxidation and hydroxylation.2
Additionally, conjugation with glucuronide acid or sulfate (phase II) has also been described.2
Resulting metabolites have been shown to exhibit reduced pharmacological activity to the parent agent (17-keto derivative) with others showing substatially reduced activity.1
The half-life of elimination of fulvestrant (250 mg) is about 40 days in adults and slightly less than twice as long for children (2-8.5 years old).
The primary route of drug excretion is through the feces (about 90%).17
Fulvestrant exhibits a distinct mechanism of action compared to selective estrogen receptor modulators (SERMs).
Although fulvestrant binds to the estrogen receptor (like SERMs), the alkylamide side chain alters estrogen receptor function.
Since fulvestrant and SERMs bind to the estrogen receptor and induce receptor dimerization, fulvestrant effects are more likely due to interactions of the drug-estrogen receptor complex with other downstream molecular components (e.g. coactivators/corepressors).
As a result of these downstream effects, the estrogen receptor is no longer capable of binding to DNA and estrogen receptor elimination is enhanced.
Elimination proceeds by proteosomal degradation, resulting in notable decreases in estrogen receptor protein concentration.
Therefore, fulvestrant totally blocks estrogen receptor-mediated gene transcription.
Fulvestrant, therefore inhibits tamoxifen-resistant breast cancer cell lines.
Fulvestrant activity is not limited to breast tissue as, for example, the drug is an absolute inhibitor of estrogen stimulation localized in uterine tissue.
Fulvestrant exhibits additional mechanisms that may account for antiproliferative activity.
For example, fulvestrant suppresses insulin -like growth factor signaling.
Additionally, this agent also inhibits the enzyme aromatase which may add to its clinical activity.2
Fulvestrant is used clinically in postmenopausal women whose metastatic breast cancer both expresses the estrogen receptor (HR+) and has progressed despite first-line antiestrogen treatment (e.g. tamoxifen or an aromatase inhibitor (AI).
Combining fulvestrant with a CDK4/6 inhibitor (palbociclib) appears to prolonged disease-free survival.1
Fulvestrant is considered well tolerated by the patient.1
Common adverse effects include:
A possible side effect is osteoporosis, noted in preclinical investigations.
Hot flashes associated with fulvestrant administration was noted in clinical trials and was usually found similar in likelihood to that observed with the aromatase inhibitors.
Most frequently observed adverse effects in the setting of metastatic breast cancer treatment (clinical trials) were gastrointestinal side effects and hot flashes.