Inhibition of prostate tumor growth in two rat models by chronic administration of D-Trp6 analogue of luteinizing hormone-releasing hormone.

Abstract

days decreased the weights of both the ventral prostate and testes but had no effect on the weight ofthe anterior pituitary gland. The percentage increase in tumor volume was decreased to one-third and the actual tumor weight was decreased by 58% compared to untreated controls. The tumor doubling time was more than 4 times longer in rats receiving D-Trp6-LH-RH than in controls. Serum levels of luteinizing hormone and follicle-stimulating hormone were significantly decreased in rats receiving this analogue. In both Fisher 344 and Copenhagen F-I rats, serum prolactin and testosterone levels were significantly decreased after treatment with D-Trp6-LH-RH, whereas progesterone levels were increased.Modification of the luteinizing hormone-releasing hormone (LH-RH) decapeptide by replacing the glycine in the 6 position by various D amino acid residues produces analogues with far greater gonadotropin-releasing activity. in vivo and in vitro than the natural hormone (1-3). Among these superactive analogues is D-Trp6-LH-RH (1), which has been tested in animals (4) as well as in humans (5, 6). Although an acute injection of superactive analogues of LH-RH causes a marked and prolonged release of gonadotropins, paradoxically, chronic administration results in chemical castration as evidenced by decreased estrogen levels and atrophy of the ovaries and uterus in female rats and by a decrease in plasma testosterone and weights of testes and accessory sex organs in male rats (7,8). These paradoxical inhibitory effects, induced by chronic administration of superactive analogues of LH-RH, have been linked with the regression of the growth of 7,12-dimethylbenzen[a]anthracene-induced mammary carcinomas in the rat (9-12). In one study, an LH-RH analogue proved to be as effective as ovariectomy or tamoxifen treatment in causing regression of these tumors which were estrogen-receptor positive (11).Lamberts et aL (13) showed that administration of either tamoxifen or a potent LH-RH agonist significantly inhibited the growth of transplantable prolactin-secreting rat pituitary tumors, but by different mechanisms. They suggested that tamoxifen acts by blocking estrogen receptors of the tumor, whereas the LH-RH agonist induces a chemical castration. These studies (9-13) indicate that chronic administration of large doses ofLH-RH agonists may inhibit the growth ofsteroiddependent tumors by suppressing both pituitary and gonadal functions.The present study compares the effect of chronic administration of D-Trp6-LH-RH on the growth of two distinct hormone-sensitive prostate tumors in the rat. Some ofour findings have appeared in abstract form (14).MATERIALS AND METHODS Male Fisher 344 rats with body weights between 100 and 120 g were inoculated subcutaneously in the scapular region with cubes (2-3 mm3) of squamous cell prostate tumor 11095 obtained from A. Segaloff (15) (Ochsner Foundation Hospital, New Orleans). D-Trp6-LH-RH was synthesized by solid-phase methods and purified as described (1) or by classical synthesis and supplied by Ayerst L...

Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

“…This is probably because deslorelin is not cytotoxic to the cells. However, LHRH superagonists such as deslorelin might inhibit tumor growth after prolonged treatment by suppressing production of testosterone, which is implicated in tumor growth (44). Other studies have shown that LHRH analogues act on tumor cells by interfering with the tyrosine kinase activity (45).…”

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

“…Similarly, the existence of this receptor was demonstrated in mouse and rat nude models (103,104), as well as in human prostate cancer biopsy (99). Based on the above evidence, several research groups have been employing GnRH analogs as antineoplastic drugs (102,(105)(106)(107)(108)(109). GnRHR and GnRH in prostate cancer are able to promote a high diminution in cellular proliferation (100,101).…”

Preparation, characterization, and biodistribution study of technetium-99m-labeled leuprolide acetate-loaded liposomes in ehrlich ascites tumor-bearing mice

“…[1][2][3][4][5][6][7] GnRH agonists induce cell cycle arrest in the Go/G1 phase, but the detailed molecular mechanism is unknown. One of the proposed mechanisms of the antitumor effect of GnRH agonists is the downregulation of GnRH receptor (GnRH-R) activity in the pituitary gland that results in inhibition of sex steroid secretion in patients with premenopausal breast cancer or prostate cancer.…”