Insulin-like growth factor-II participates in the biphasic effect of a gonadotropin-releasing hormone agonist on ovarian cancer cell growth.
OBJECTIVE
To examine the involvement of insulin-like growth factors (IGFs) in growth regulation of an ovarian cancer cell line and to investigate whether the GnRH agonist tryptorelin might influence a potential autocrine or paracrine loop involving IGFs.


METHODS
In vitro, prospective, randomized controlled study.


METHODS
In vitro experiments at the Section of Gynecologic Oncology, Surgery Branch, National Cancer Institute.


METHODS
None. Human ovarian adenocarcinoma cell line IGROV-1.


METHODS
The proliferative effect of tryptorelin on IGROV-1 cells was analyzed by using the MTT (93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide) colorimetric assay. The ribonuclease protection assay was used to investigate whether an autocrine pathway involving IGF-I or IGF-II might participate in the growth of these cells. The expression of GnRH receptor was assessed by the 125I-GnRH binding assay.


METHODS
Changes in cell growth and expression of IGF-I and IGF-II messenger RNA (mRNA).


RESULTS
Tryptorelin exhibited a bimodal, dose- and time-dependent effect on IGROV-1 cells when compared with untreated control cells: Cellular proliferation was enhanced during the first 24 hours of exposure, but longer incubations resulted in growth inhibition. The mitogenic effect of tryptorelin was inhibited when cells were co-incubated with either IGF binding protein-5 (IGFBP-5) or anti-IGF-II antibody, which can both bind to IGF-II and neutralize it. Insulin-like growth factor-I mRNA was not detected in IGROV-1 cells. However, IGF-II transcripts were detected after incubation with tryptorelin for 12 hours, but thereafter, no mRNA was observed, even after prolonged exposure. Binding analysis revealed a specific, high-affinity GnRH binding site.


CONCLUSIONS
These data suggest that tryptorelin exerts a bimodal growth effect on ovarian cancer cells by a mechanism involving the autocrine production of IGF-II. The effect of tryptorelin on IGF-II gene transcription in these ovarian cancer cells appears to mirror the desensitizing effects of prolonged GnRH exposure on pituitary gonadotropin production.
Ho
M N
MN
Section of Gynecologic Oncology, National Cancer Institute, Bethesda, Maryland 20892-1502, USA.
Delgado
C H
CH
Owens
G A
GA
Steller
M A
MA
D000230:Adenocarcinoma / Q000473:pathology*; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008934:Mitogens / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D017329:Triptorelin Pamoate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D018975:Insulin-Like Growth Factor Binding Protein 5; D008934:Mitogens; D012333:RNA, Messenger; D017329:Triptorelin Pamoate; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II