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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

Antineoplastic Agents: Hormone Derivatives

Tamoxifen (Nolvadex) is a synthetic antiestrogen used in the treatment of breast cancer.






Tamoxifen (Nolvadex) is a synthetic antiestrogen  used in the treatment of breast cancer. Normally, estrogens act by binding to a cytoplasmic pro-tein receptor, and the resulting hormone–receptor com-plex is then translocated into the nucleus, where it induces the synthesis of ribosomal RNA (rRNA) and messenger RNA (mRNA) at specific sites on the DNA of the target cell. Tamoxifen also avidly binds to estrogen receptors and competes with endogenous estrogens for these critical sites. The drug–receptor complex has little or no estrogen ago-nist activity. Tamoxifen directly inhibits growth of human breast cancer cells that contain estrogen receptors but has little effect on cells without such receptors.


Tamoxifen is slowly absorbed, and maximum serum levels are achieved 4 to 7 hours after oral administration.

The drug is concentrated in estrogen target tissues, such as the ovaries, uterus, vaginal epithelium, and breasts. Hydroxylation and glucuronidation of the aromatic rings are the major pathways of metabolism; excretion occurs primarily in the feces.


The presence of estrogen receptors (ER) in biopsies of breast cancers is a good predictor of responsiveness to tamoxifen therapy: 60% of women with ER-positive tumors will have a remission, as opposed to fewer than 10% with ER-negative tumors. Overall, 35 to 40% of women with breast cancer will respond to some degree, with antitumor effects lasting an average of 9 to 12 months. Complete remissions may occur in 10 to 15% of patients and may last several months to a few years. Therapy should be continued for at least 6 weeks to es-tablish efficacy.


Tamoxifen administration is associated with few toxic side effects, most frequently hot flashes (in 10–20% of patients) and occasionally vaginal dryness or discharge. Mild nausea, exacerbation of bone pain, and hypercalcemia may occur.




Estramustine phosphate sodium (Emcyt) is a hybrid structure combining estradiol and a nitrogen mustard in a single molecule. The drug has been approved for use in prostatic carcinomas and will produce clinical remis-sions in one-third of patients who have failed to re-spond to previous estrogen therapy. The mechanism of action of estramustine is not well defined, but it does not appear to require either alkylation of DNA or the presence of estrogen receptors in tumor cells. Nonetheless, the toxicities of the drug are similar to those of estrogen therapy: breast tenderness and en-largement (gynecomastia), fluid retention, mild nausea, and an increased risk of thrombophlebitis and pul-monary embolism. The drug is not myelosuppressive.




Flutamide (Eulexin) is a nonsteroidal antiandrogen  compound that competes with testosterone for binding to androgen receptors. The drug is well ab-sorbed on oral administration. It is an active agent in the hormonal therapy of cancer of the prostate and has been shown to complement the pharmacological castra-tion produced by the gonadotropin-releasing hormone (GnRH) agonist leuprolide. Flutamide prevents the stimulation of tumor growth that may occur as a result of the transient increase in testosterone secretion after the initiation of leuprolide therapy. The most common side effects of flutamide are those expected with andro-gen blockade: hot flashes, loss of libido, and impotence. Mild nausea and diarrhea occur in about 10% of pa-tients.

Buserelin and Leuprolide


Buserelin (Suprefact) and leuprolide (Lupron) are pep-tide analogues of the hypothalamic hormone LH-RH (luteinizing hormone–releasing hormone). Chronic ex-posure of the pituitary to these agents abolishes go-nadotropin release and results in markedly decreased estrogen and testosterone production by the gonads. Their major clinical use is in the palliative hormonal therapy of cancer of the prostate.


Leuprolide is a potent LH-RH agonist for the first several days to a few weeks after initiation of therapy, and therefore, it initially stimulates testicular and ovar-ian steroidogenesis. Because of this initial stimulation of testosterone production, it is recommended that pa-tients with prostatic cancer be treated concurrently with leuprolide and the antiandrogen flutamide (discussed earlier). Leuprolide is generally well tolerated, with hot flashes being the most common side effect.


Somatostatin Analogue


Octreotide acetate (Sandostatin) is a synthetic peptide analogue of the hormone somatostatin. Its actions in-clude inhibition of the pituitary secretion of growth hormone and an inhibition of pancreatic islet cell secre-tion of insulin and glucagon. Unlike somatostatin, which has a plasma half-life of a few minutes, octreotide has a plasma elimination half-life of 1 to 2 hours. Excretion of the drug is primarily renal.


Octreotide is useful in inhibiting the secretion of various autacoids and peptide hormones by metastatic carcinoid tumors (serotonin) and islet cell carcinomas of the pancreas (gastrin, glucagon, insulin, vasoactive in-testinal peptide). The diarrhea and flushing associated with the carcinoid syndrome are improved in 70 to 80% of the patients treated with octreotide. Its side effects, which are usually mild, include nausea and pain at the injection site. Mild transient hypoglycemia or hyper-glycemia may result from alterations in insulin, glucagon, or growth hormone secretion.


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