Evidence that 2-methoxyestradiol suppresses proliferation and accelerates apoptosis in normal rat growth plate chondrocytes.
OBJECTIVE
2-Methoxyestradiol (2ME(2)), a metabolite of 17beta-estradiol, is currently undergoing extensive clinical testing as an antitumor agent. This drug antagonizes both angiogenesis and induces apoptosis in some tumor cell lines. Growth plate alterations as well as an inhibition of longitudinal bone growth have been reported in young rats treated with a pharmacological dose of 2ME(2). However, 2ME(2)'s mechanism of action at the growth plate is unknown. To uncover the mechanism, we examined the dose-response effects of 2ME(2) on growth plate chondrocytes.


METHODS
2ME(2) (4-, 20-, and 75 mg.kg.day) was administered orally to recently ovariectomized 10-week-old rats. The number of cells undergoing DNA synthesis was evaluated with (3)H-thymidine radioautography, apoptosis-induced DNA fragmentation was detected with TUNEL assay, and longitudinal growth rates were determined with fluorochrome labeling.


RESULTS
2ME(2) reduced bone elongation ( P< or =0.05), suppressed chondrocyte proliferation ( P< or =0.05), and induced chondrocyte apoptosis ( P< or =0.05). Furthermore, 1-week treatment with 2ME(2) did not affect the size of hypertrophic chondrocytes.


CONCLUSIONS
Thus, pharmacological doses of 2ME(2) utilized for tumor suppression can inhibit normal bone elongation in growing rats by reducing the number of proliferating chondrocytes in the growth plate and accelerating apoptosis in differentiated chondrocytes. This demonstration identifies another organ in which toxicity should potentially be monitored in ongoing and future clinical trials of 2ME(2).
Sibonga
Jean D
JD
Department of Orthopedics, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA, Sibonga.Jean@mayo.edu
Sommer
Ulrike
U
Turner
Russell T
RT
D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis; D001345:Autoradiography; D002455:Cell Division; D019902:Chondrocytes / Q000187:drug effects*; D046508:Culture Techniques; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000166:cytology; D006132:Growth Plate / Q000166:cytology* / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D051381:Rats
D004958:Estradiol; D000077584:2-Methoxyestradiol
Non-programmatic