Medical Pharmacology Chapter 33-34: Anticancer Drugs
Natural Products: Microtubule Antagonists
Estramustine Phosphate (Emcyt)
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Estramustine phosphate is classified as a microtubule antagonist and consists of a combination of 17 β-estradiol and normustine (nornitrogen mustard).1,10
A carbamate ester linkage connects the two moieties.
The combination of an alkylating agent and estradiol was intended to firstly target estradiol-sensitive prostate cancer and secondly to exert antineoplastic effects by means of alkylation.
However, the antineoplastic activity of estramustine does not depend on alkylation but rather on association with β-tubulin and microtubule-associated proteins (MAP).
This interaction with microtubules related structures and proteins promotes loss of microtubule structural integrity and cause antimitotic effects.1
The singular clinical use of estramustine phosphate is in the management of individuals with prostate cancer, either metastatic or hormone-refractory.1
Absorption, Distribution, Biotransformation, Excretion:10
Following oral administration, most (75%) of estramustine phosphate is first absorbed from the G.I. tract and then undergoes rapid dephosphorylation.10
The agent (after oral administration) is subject to substantial first-pass metabolism catalyzed by the liver cytochrome P450 drug metabolizing system.
Hepatic metabolism results in various inactive products as well as an active 17-keto derivative and estromustine.
Accumulation and action of both estramustine phosphate and the metabolite estromustine are dependent on expression of a binding protein, estramustine-binding protein (EMBP).
Hepatic metabolism (cytochrome P450 dependent) results in oxidative metabolism of estramustine to estromustine, a major active estramustine phosphate metabolite.
Maximal plasma estromustine concentration is noted in about three hours following oral administration with the elimination half-life of estromustine being about 12 hours.
Both estromustine and estromustine are excreted in the feces primarily with limited conjugated estrone and estradiol noted in the urine (<1%).10
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Estromustine binds to beta-tubulin at a location different from that observed with either colchicine or vinca alkaloids.
Following binding, microtubule and microfilaments depolymerization is noted along with disruption of microtubule associated proteins.
At high drug concentrations, cellular growth is inhibited reflecting mitotic arrest and tumor cell apoptosis (programmed cell death).
The singular clinical use of estramustine phosphate is in the management of individuals with prostate cancer, either metastatic or hormone-refractory.1
Patients with hormone-refractory prostate cancer with bone pain may be effectively managed, pallitavely, by a combination of mitoxantrone and prednisone.3
Estromustine by itself exhibits about a 20% response rate when given as a single agent.
When estromustine is used along with either a taxane (paclitaxel or docetaxel) or etoposide, response rates increase to about 45%.
With respect to overall survival advantage, a comparison of the docetaxel prednisone combination with the mitoxantrone-prednisone protocol indicated that the former was comparatively advantageous.
Therefore, docetaxel along with prednisone represent standard of care in management of hormone-refractory prostate cancer.3
Side Effects:1,10
Administration of estramustine phosphate only rarely results in clinically important myelosuppression.
Nausea and vomiting represent principal toxicities.
Estromustine dosing does, however, result in estrogenic effects such as:
Gynecomastia
Impotence
Nipple tenderness
Increased thrombosis risk (thromboembolic complications may be noted in up to 10% of patients)
Fluid retention
Acute porphyria attacks
Decreased glucose tolerance
Hypersensitivity reactions such as angioedema.