Inhibition of growth of human mammary tumor cells by potent antagonists of luteinizing hormone-releasing hormone.

Abstract

Various studies support the view that analogs of luteinizing hormone-releasing hormone (LH- des-Gly10-[D-Ser(tBu)6]LH-RH ethylamide (buserelin) had no effect. The antagonists SB-29 and SB-30 also inhibited the rate of cell growth, as measured by cell number, while the LH-RH agonist buserelin had no significant effect. These results support the concept that these new LH-RH antagonists can directly inhibit the growth of human mammary tumors and thus might be suitable for the treatment of breast cancer.RHChronic administration of potent agonists of luteinizing hormone-releasing hormone (LH-RH) results in the inhibition of pituitary and gonadal function (1, 2) and creates a state of sex-steroid deficiency. Consequently, agonists of LH-RH can be used for the treatment of some hormone-dependent tumors, such as prostatic and breast cancer (1, 2). In view of many expected medical applications of LH-RH derivatives, more than 2000 analogs have been synthesized since the isolation and structural elucidation of LH-RH (3). Many agonistic analogs more potent than the parent hormone have been made (1, 2, 4). Several of these agonists are being used clinically (1, 2, 5). Potent inhibitory analogs of LH-RH, which block ovulation in laboratory animals, have also been synthesized (4). Several antagonists of LH-RH have been tested in men and women and shown to be active enough for practical use (4). LH-RH antagonists may offer certain advantages in the treatment of cancer as compared with the superagonists. While a repeated administration of LH-RH agonists is required to inhibit the pituitary and gonadal function and reduce the levels of sex steroids, the same effect may be obtained by a single administration of LH-RH antagonists (4). The inhibition of gonadotropin release by LH-RH antagonists starts immediately after its administration, while the agonists cause a transient stimulation of pituitary and gonadal function, which may result in a temporary clinical "flare-up" of the disease (5).LH-RH antagonists are frequently characterized by the nature of the residue at position 6. Some potent LH-RH antagonists contained D-arginine (hydrophilic basic substitution) at this position. However, this class of analogs produced transient edema of the face and extremities when administered subcutaneously to rats (6, 7). In preliminary human tolerance studies, side effects were also observed in some cases after administration of antagonists with basic D-amino acids at position 6. These reactions could be due to histamine liberation. These side effects delayed clinical use of LH-RH antagonists in humans.To MATERIALS AND METHODSPeptides. Buserelin was a gift from J. Sandow (Hoechst), ORG 30276 was obtained from L. Tax (Organon), the antagonists SB-29 and SB-30 were synthesized and purified in the Veterans Administration/Tulane University laboratory as reported (4). 1648The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U....

Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation

“…It has also been reported that treatment of thymocytes, splenocytes, and lymphocytes with GnRH and its analogues increased their proliferative activity (Marchetti et al ., 1989;Batticane et al ., 1991;Azad et al ., 1997). In these studies the effects of GnRH on cell proliferation were investigated by measuring tumor weight and/or volume, the rate of cell proliferation, or 3 H-thymidine incorporation (Redding and Schally, 1983;Sharoni et al ., 1989;Pati and Habibi, 1995;Dondi et al ., 1998). However, to our knowledge, there have been no studies that compared stimulatory with inhibitory effects.…”

Inhibition of human epithelial ovarian cancer cellgrowth in vitro by agonistic and antagonistic analogues of luteinizinghormone-releasing hormone.

“…The presence of LH-RH receptors in ovarian cancer suggests that LH-RH analogs could exert direct inhibitory effects on the growth of ovarian cancers (11). Previously, some direct action of LH-RH analogs was also proposed in the case of prostate and breast cancers (22)(23)(24).…”

Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist Cetrorelix with growth inhibition

“…These experimental results suggest a regulatory role for LHRH-like peptides on tumor growth (14,18,21,27,28). Consequently LHRH antagonists like Cetrorelix could be considered for the development of new therapies for LHRH receptor positive cancers (17).…”

“…This concept is supported by an inhibitory effect of LHRH agonists and LHRH antagonist Cetrorelix on human mammary, prostatic, ovarian and endometrial cancer cell lines in vitro through specific tumoral LHRH receptors under conditions which exclude effects through the pituitary and the gonads (14,15,(18)(19)(20). Particularly relevant could be the demonstration of the inhibitory effects of Cetrorelix on growth of MDA-MB-231 and MCF-7 human breast cancer cells in vitro (21)(22)(23)(24)(25).…”