Lec 12 Steroid Hormones and Their Antagonists (antitumor)
Tumors that are sensitive to steroid hormones may be either
1-hormone responsive, in which the tumor regresses following treatment with a
specific hormone; or
2-hormone dependent, in which removal of a hormonal stimulus causes tumor
regression; or
3- Both.
Removal of hormonal stimuli from hormone-dependent tumors can be
accomplished by surgery (for example, in the case of orchiectomy—surgical
removal of one or both testes—for patients with advanced prostate cancer) or by
drugs (for example, in breast cancer treatment with the antiestrogen tamoxifen
prevents estrogen stimulation of breast cancer cells). For a steroid hormone to
influence a cell, that cell must have intracellular (cytosolic) receptors that are
specific for that hormone.
A. Tamoxifen
Tamoxifen is a selective estrogen modulator (SERM).
It is an estrogen antagonist in breast tissue and an agonist in other tissues, such as
bone and the [Link] is used for first-line therapy in the treatment
of estrogen receptor–positive breast cancer. It is also used for prevention of breast
cancer in high-risk women.
Mechanism of action
Tamoxifen competes with estrogen for binding to estrogen receptors in the breast
tissue, and inhibits estrogen induced growth of breast cancer.
The result is
• depletion (down-regulation) of estrogen receptors, and the
• growth-promoting effects of the natural hormone and other growth factors
are suppressed.
Pharmacokinetics
Tamoxifen is effective after oral administration. It is partially metabolized by the
liver. Some metabolites possess estrogen antagonist activity, whereas others have
agonist activity.
Unchanged drug and metabolites are excreted predominantly through the bile into
the feces. Tamoxifen is an inhibitor of CYP3A4 and P-glycoprotein.
Adverse effects
Adverse effects caused by tamoxifen include : Hot flashes, nausea, vomiting, skin
rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and
some of its metabolites in the endometrial tissue).Tamoxifen has the potential to
cause endometrial cancer, thromboembolism and effects on vision.
B. Fulvestrant and raloxifene
Fulvestrant is an estrogen receptor antagonist that is given via IM injection to
patients with hormone receptor–positive metastatic breast cancer. This agent binds
to and causes estrogen receptor down regulation on tumors and other targets.
Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast
tissues, while promoting effects in the bone to inhibit resorption. This agent
reduces the risk of estrogen receptor–positive invasive breast cancer in
postmenopausal women. Both drugs are known to cause hot flashes, arthralgias,
and myalgias.
C. Aromatase inhibitors
The aromatase reaction is responsible for extra-adrenal synthesis of estrogen from
androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues,
including breast malignancies.
Peripheral aromatization is an important source of estrogen in postmenopausal
women. Aromatase inhibitors decrease the production of estrogen in these women.
1. Anastrozole and letrozole
Anastrozole and letrozole are nonsteroidal aromatase inhibitors.
These agents are considered first-line drugs for the treatment of breast cancer in
postmenopausal women. They are orally active and cause almost a total
suppression of estrogen synthesis.
Anastrozole and letrozole do not predispose patients to endometrial cancer.
Both drugs are extensively metabolized in the liver, and metabolites and parent
drug are excreted primarily in the urine.
2. Exemestane
A steroidal, irreversible inhibitor of aromatase,
Exemestane, is well absorbed after oral administration and widely distributed.
Hepatic metabolism occurs via the CYP3A4 isoenzyme. Because the metabolites
are excreted in urine, doses of the drug must be adjusted in patients with renal
failure.
Major toxicities are nausea, fatigue, and hot flashes. Alopecia and dermatitis have
also been noted.
D. Leuprolide, goserelin, and triptorelin
Gonadotropin-releasing hormone (GnRH) is normally secreted by the
hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic
hormones:
1-Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone
by the testes, and
2-Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen.
Leuprolide, goserelin, and triptorelin are synthetic analogs of GnRH.
As GnRH analogs, they occupy the GnRH receptor in the pituitary, which leads to
its desensitization and, consequently, inhibition of release of FSH and LH. Thus,
both androgen and estrogen synthesis are reduced. Response to leuprolide in
prostatic cancer is equivalent to that of orchiectomy with regression of tumor and
relief of bone pain.
These drugs have some benefit in premenopausal women with advanced breast
cancer and have largely replaced estrogens in therapy for prostate cancer.
Leuprolide is available as:
1) A subcutaneous daily injection,
2) A subcutaneous depot injection, or
3) An intramuscular depot injection to treat metastatic carcinoma of the prostate.
Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected
intramuscularly. Levels of androgen in prostate cancer patients may initially rise,
but then fall to castration levels.
The adverse effects of these drugs, including
Impotence, hot flashes, and tumor flare, are minimal compared to those
experienced with estrogen treatment.
E. Antiandrogens
Flutamide, nilutamide, bicalutamide, and enzalutamide are oral antiandrogens
used in the treatment of prostate cancer. They compete with the natural hormone
for binding to the androgen receptor and prevent its action in the prostate
Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain.
Rarely, liver failure has occurred with flutamide. Nilutamide can cause visual
problems.
Platinum Coordination Complexes
A. Cisplatin, carboplatin, and oxaliplatin
Cisplatin was the first member of the platinum coordination complex class of
anticancer drugs, but because of severe toxicity, carboplatin was developed.
Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic
agents. It has found wide application in the treatment of solid tumors, such as
metastatic testicular carcinoma in combination with VBL and bleomycin,
ovarian carcinoma in combination with cyclophosphamide, or alone for bladder
carcinoma.
Carboplatin is used when patients cannot be vigorously hydrated, as is required
for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to
neuro- or ototoxicity.
Oxaliplatin is a closely related analog of carboplatin used in the setting of
colorectal cancer.
Mechanism of action
The mechanism of action of these agents is similar to that of the alkylating agents.
In the high-chloride milieu of the plasma, cisplatin persists as the neutral species,
which enters the cell and loses chloride in the low-chloride milieu. It then binds to
guanine in DNA, forming inter- and intrastrand cross-links. The resulting cytotoxic
lesion inhibits both polymerases for DNA replication and RNA synthesis.
Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable
to the actions of these drugs in the G1 and S phases.
Pharmacokinetics
These agents are administered via IV infusion. Cisplatin and carboplatin can also
be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other
organs. The highest concentrations of the drugs are found in the liver, kidney, and
intestinal, testicular, and ovarian cells, but little penetrates into the cerebrospinal
fluid (CSF). The renal route is the main pathway of excretion.
Adverse effects
Severe nausea and vomiting occurs in most patients after administration of
cisplatin and may continue for as long as 5 days. Premedication with antiemetic
agents is required. The major limiting toxicity is dose-related nephrotoxicity,
involving the distal convoluted tubule and collecting ducts. This can be prevented
by aggressive hydration. Other toxicities include ototoxicity with high-frequency
hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea
and vomiting, and it is rarely nephro-, neuro-, or ototoxic. The dose-limiting
toxicity is myelosuppression. Oxaliplatin has a distinct adverse effect of cold-
induced peripheral neuropathy that usually resolves within 72 hours of
administration. It also causes myelosuppression and cumulative peripheral
neuropathy. Hepatotoxicity has also been reported. These agents may cause
hypersensitivity reactions ranging from skin rashes to anaphylaxis.
Topoisomerase Inhibitors
These agents exert their mechanism of action via inhibition of topoisomerase
enzymes, a class of enzymes that reduce supercoiling of DNA.
A. Camptothecins
Camptothecins are plant alkaloids originally isolated from the Chinese tree
Camptotheca. Irinotecan and topotecan are semisynthetic derivatives of
camptothecin.
Topotecan is used in metastatic ovarian cancer when primary therapy has failed
and also in the treatment of small cell lung cancer. Irinotecan is used with 5-FU
and leucovorin for the treatment of colorectal carcinoma.
Mechanism of action
These drugs are S-phase specific and inhibit topoisomerase I, which is essential for
the replication of DNA in human cells. SN-38 (the active metabolite of irinotecan)
is approximately 1000 times as potent as irinotecan as an inhibitor of
topoisomerase I. The topoisomerases relieve torsional strain in DNA by causing
reversible, singlestrand breaks.
Adverse effects: Bone marrow suppression, particularly neutropenia, is the dose-
limiting toxicity for topotecan. Frequent blood counts should be performed in
patients receiving this drug. Myelosuppression is also seen with irinotecan. Acute
and delayed diarrhea with irinotecan may be severe and require treatment with
atropine during the infusion or high doses of loperamide in the days following the
infusion.
B. Etoposide
Etoposide is a semisynthetic derivative of the plant alkaloid, podophyllotoxin.
This agent blocks cells in the late S to G2 phase of the cell cycle, and the major
target is topoisomerase II. Binding of the drug to the enzyme–DNA complex
results in persistence of the transient, cleavable form of the complex and, thus,
renders it susceptible to irreversible double-strand breaks.
Etoposide finds its major clinical use in the treatment of lung cancer and in
combination with bleomycin and cisplatin for testicular carcinoma. Etoposide may
be administered either IV or orally. Dose-limiting myelosuppression (primarily
leukopenia) is the major toxicity.
Monoclonal antibodies
Monoclonal antibodies are an active area of drug development for anticancer
therapy and other nonneoplastic diseases, because they are directed at specific
targets and often have different adverse effect profiles as compared to traditional
chemotherapy agents. All of these agents are administered intravenously, and
infusion-related reactions are common.
Tyrosine Kinase Inhibitors
The tyrosine kinases are a family of enzymes that are involved in several important
processes within a cell, including signal transduction and cell division. The
tyrosine kinase inhibitors are administered orally, and these agents have a wide
variety of applications in the treatment of cancer.
Immunotherapy
Immunotherapy with intravenous immune checkpoint inhibitors is a rapidly
evolving option for cancer treatment. The goal of immune checkpoint inhibitors is
to block the checkpoint molecules, such as the programmed death (PD-1) receptor,
that normally help to keep the immune system in check. By blocking these
molecules, the immune system is better able to attack the tumor and cause
destruction. The two most commonly used checkpoint inhibitors are
pembrolizumab and nivolumab. The adverse reaction profiles of these agents
consist of potentially severe and even fatal immune-mediated adverse events. This
is because turning off the immune checkpoints allows attack of the tumor, but can
also lead to unchecked autoimmune response to normal tissues.
Adverse events include diarrhea, colitis, pneumonitis, hepatitis, nephritis,
neurotoxicity, dermatologic toxicity in the form of severe skin rashes, and
endocrinopathies such as hypo- or hyperthyroidism. Patients should be closely
monitored for the potential development of signs and symptoms of toxicity and
promptly treated with corticosteroids if necessary.
Miscellaneous Agents
Abiraterone acetate
Abiraterone acetate is an oral agent used in the treatment of metastatic castration–
resistant prostate cancer. Abiraterone acetate is used in conjunction with
prednisone to inhibit the CYP17 enzyme (an enzyme required for androgen
synthesis), resulting in reduced testosterone production. Coadministration with
prednisone is required to help lessen the effects of mineralocorticoid excess
resulting from CYP17 inhibition.
Hepatotoxicity may occur, and patients should be closely monitored for
hypertension, hypokalemia, and fluid retention. Joint and muscle discomfort, hot
flushes, and diarrhea are common adverse effects with this agent.
Immuno-modulating agents
Thalidomide, lenalidomide, and pomalidomide are oral agents used in the
treatment of multiple myeloma. Their exact mechanism of action is not clear, but
they possess antimyeloma properties including antiangiogenic, immune-
modulation, anti-inflammatory and antiproliferative effects. These agents are often
combined with dexamethasone or other chemotherapeutic agents.
Adverse effects include thromboembolism, myelosuppression fatigue, rash, and
constipation. Thalidomide was previously given to pregnant women to prevent
morning sickness. However, severe birth defects were prevalent in children born to
mothers who used thalidomide. Because of their structurally similarities to
thalidomide, lenalidomide and pomalidomide are contraindicated in pregnancy.
Proteasome inhibitors
Bortezomib, Ixazomib, and Carfilzomib are proteasome inhibitors commonly
used as the backbone therapy in the treatment of multiple myeloma. These agents
work by inhibiting proteasomes, which in turn prevents the degradation of
proapoptotic factors, thus leading to a promotion in programmed cell death
(apoptosis).
Malignant cells readily depend on suppression of the apoptotic pathway; therefore,
proteasome inhibition works well in multiple myeloma.
Bortezomib can be administered IV, but the subcutaneous route is preferred
because it is associated with less neuropathy. Other adverse effects include
myelosuppression, diarrhea, nausea, fatigue, and herpes zoster reactivation.
Patients should receive antiviral prophylaxis if they are receiving therapy with
bortezomib.
Ixazomib is an oral agent with an adverse effect profile similar to bortezomib.
Carfilzomib is administered intravenously, and common adverse effects include
myelosuppression, fatigue, nausea, diarrhea, and fever.
