Hormone-independent, non-alkylating mechanism of cytotoxicity for estramustine.
Over two decades, experience with estramustine has provided limited data which support an estrogenic mechanism of action and no data which indicate the nitrogen mustard involvement in the cytotoxic properties of the drug. Consideration of the carbamate-ester portion of estramustine supports the pharmacokinetic evidence that estramustine has a long half life since enzymatic hydrolysis of the carbamate is an uncommon event. Using a variety of immunocytochemical and cellular morphology procedures, estramustine per se has been found to express anti-cytoskeletal properties through non-covalent binding to microtubule associated proteins (MAP's). In both fish erythrophores and in dividing human prostatic carcinoma cells, estramustine exerts an antimicrotubule effect at micromolar concentrations. Thus, estramustine possesses unique pharmacology and protein binding specificity. As such, it should not be classified as an alkylating agent. The estrogenic effects, while possibly of relevance to clinical administration, are not the primary mechanism by which the drug exerts cytotoxicity.
Tew
K D
KD
Stearns
M E
ME
D000478:Alkylation; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004961:Estramustine / Q000494:pharmacology / Q000633:toxicity*; D005399:Fishes; D005455:Fluorescent Antibody Technique; D006728:Hormones / Q000502:physiology*; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D009588:Nitrogen Mustard Compounds / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D012867:Skin / Q000166:cytology; D014410:Tumor Stem Cell Assay
D006728:Hormones; D009588:Nitrogen Mustard Compounds; D004961:Estramustine