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Kakar Sham S; Nath, Sati; Bunn, Jason; Jennes, Lothar
Anti-Cancer Drugs: April 1997
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Gonadotropin releasing hormone (GnRH) and its analogs inhibit the growth of hormone-dependent tumors in vivo and in vitro. The inhibition of growth and proliferation of tumor cells in vitro by GnRH and its analogs indicates that the tumor suppressing effect of the hormone is only partially due to suppression of pituitary gonadotropin release which reduces circulating steroid levels that are required for proliferation. Demonstration of GnRH-binding sites on some tumors suggests a direct inhibitory effect of GnRH and its analogs. However, the mechanism by which GnRH and its analogs inhibit tumor cell growth is not known. Our hypothesis is that the inhibition of growth and proliferation of tumor cells by GnRH and its analogs are mediated through down-regulation of its receptor expression. To test this hypothesis, mouse pituitary gonadotrope cell line (αT3-1) was selected as a model since this is the only cell line which expresses a sufficiently high level of GnRH receptors for precise measurements of the mRNA for the receptor. Addition of GnRH agonist (D-Lys6)GnRH to the cell cultures caused a time-dependent decrease in both cell growth, as measured by cell number, and cell proliferation, as measured by [3H]thymidine incorporation into DNA. After 1 h of treatment of aT3-1 cells with 1 //M of (DLys6) GnRH, the cell number was reduced to 83.0 ±13.4 compared to control, decreased to 75.1 ± 3.2 at 2 h, 63.2 ± 0.66 at 4 h and 52.2 ± 0.87 at 24 h. This decrease in cell number was accompanied by a parallel decrease in [3H]thymidine incorporation into DNA. The inhibition of cell growth and [3H]thymidine incorporation by treatment with 1 fiM of (D-Lys6)GnRH was sustained for at least 72 h. Inhibition of aT3-1 cell growth and [3H]thymidine incorporation was dose-dependent; thus 10~9 M (D-Lys6)GnRH resulted in about 30% inhibition within 4 h which was comparable to 10-6 M (D-Lys6)GnRH, whereas 10-12 M (DLys6) GnRH was ineffective. Measurement of mRNA for the GnRH receptor by Northern blot analysis showed a decrease in levels of mRNA by 5% within 2 h of treatment of aT3-1 cells with 1 µM (D-Lys6)GnRH, by 30% at 4 h and by 50% at 24 h. In conclusion these data demonstrate that treatment of aT3-1 cells with (D-Lys6)GnRH causes an inhibition of cell growth and proliferation, and downregulates the GnRH receptor mRNA levels.

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