Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Microtubule Antagonists

  • Estramustine Phosphate (Emcyt)

    • Estramustine Phosphate (Emcyt)

     

    • Overview:

      • 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

              •  

                Estramustine phosphate metabolism

                Estramustine phosphate metabolism Attribution:  Medgirl131 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)] https://commons.wikimedia.org/wiki/File:Estramustine_phosphate_metabolism.png

    • Mechanism of Action:

      • 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).

    • Clinical use:

      • 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.