The effect of "activated" cyclophosphamide on rat granulosa cells in vitro.
We investigated the mechanism of cyclophosphamide (CTX)-induced ovarian toxicity by studying the effect of an activated form, 4-hydroperoxycyclophosphamide (PCTX), on rat granulosa cells in vitro. Cells were obtained from PMSG-primed immature rats and incubated with PCTX at concentrations of 1, 10, 100, and 500 micrograms/mL. Ovine LH (10 ng/mL) was added in selected tubes. Cell viability before and after seven hours incubation was determined. Progesterone and prostaglandin E accumulation were measured by radioimmunoassay. Granulosa cell viability was significantly decreased at PCTX concentrations of 10 micrograms/mL or higher in a dose-related manner. PCTX at concentrations of 100 micrograms/mL and 500 micrograms/mL significantly decreased basal and LH-induced progesterone and prostaglandin E accumulation. The above findings demonstrate that cyclophosphamide metabolites decrease granulosa cell survival and function in vitro. These direct effects suggest a possible mechanism for CTX-induced premature ovarian failure.
Ramahi-Ataya
A J
AJ
Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201.
Ataya
K M
KM
Subramanian
M G
MG
Struck
R F
RF
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects*; D066298:In Vitro Techniques; D011374:Progesterone / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D011458:Prostaglandins E; D011374:Progesterone; D003520:Cyclophosphamide; C011272:perfosfamide