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ENDOCRINE AND DIABETES
Ferring Research Ltd., Southampton, United Kingdom (M.P., P.B., J.M., G.M., L.E., R.H., C.Y.); Ferring Inc., San Diego, California (R.W.); and Ferring International Center, Copenhagen, Denmark (K.B.)
Received August 11, 2006; accepted December 18, 2006.
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Abstract |
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). In the European Community and in the United States, where both the prevalence and incidence of prostate cancer are increasing, more than 500,000 new cases are diagnosed each year, with an estimated 50,000 deaths (Kirkels and Rietbergen, 1997; Jemal et al., 2004). The number of patients with prostate cancer is expected to increase steadily over the next decade, because the average age of men is increasing and the incidence of prostate cancer increases more rapidly with age than the incidence of other cancers (Jemal et al., 2004).
A widely recognized feature of prostate cancer is its high sensitivity to testosterone deprivation. The current medical approach in the treatment of androgen-dependent prostate tumors is to suppress testosterone production using agonist analogs of the hypothalamic gonadotrophin-releasing hormone (GnRH, also known as LHRH) that control the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. Chronic administration of GnRH superagonists eventually leads to a desensitization of pituitary GnRH receptors and a corresponding inhibition of gonadotrophin and testosterone secretion (Rivier et al., 1978; Nett et al., 1981; Heber et al., 1982). However, a major drawback of agonist therapy is that it initially stimulates gonadotrophin and testosterone secretion, resulting in a surge in LH and testosterone levels for 2 to 3 weeks before castration is completed and a subsequent delay in therapeutic benefit. This temporary increase in testosterone levels can exacerbate the hormone-sensitive cancer, as well as patient symptoms, such as sudden paraplegia due to spinal cord compression by epidural metastases, exacerbation of bone pain, and urinary retention (Kahan et al., 1984). Therefore, antiandrogens are often coadministered in the initial phase of GnRH receptor agonist treatment to minimize the stimulatory effects of the testosterone surge on the prostate cancer cells (Dupont et al., 1988). Furthermore, "depot" injections may result in small bursts of androgens (acute on chronic phenomenon), which may overstimulate growth of tumors that have adapted (through gene mutations) to low levels of androgens by overactivity of androgen receptors and associated transcription factors (Langeler et al., 1993; Montgomery et al., 2001; Suzuki et al., 2003).
In the search for alternatives to superagonist therapy, researchers have been developing GnRH antagonists that suppress the release of gonadotrophins by binding competitively to pituitary GnRH receptors. GnRH antagonists do not induce the LH and testosterone surge; instead, they work directly to reduce the release of gonadotrophin and testosterone within hours. Despite the advantages of GnRH antagonists over agonists in suppressing serum gonadal steroids, many of the peptide GnRH antagonists investigated so far show histamine-releasing properties and/or solubility limitations that affect their clinical usefulness or even preclude their development as drugs (Hocart et al., 1987; Flouret et al., 1992; Bagatell et al., 1993, 1995).
Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) GnRH antagonists forming a subcutaneous gel that has only very weak histamine-releasing potential compared with other GnRH antagonists (Broqua et al., 2002; Schwach et al., 2003, 2004; Tornoe et al., 2004). When administered subcutaneously in rats and primates, degarelix immediately blocks GnRH receptors in the pituitary, resulting in fast and sustained suppression of gonadotrophin secretion with the absence of initial stimulation of the gonadotrophic axis (Broqua et al., 2002).
The present study compares the pharmacological activity of a new GnRH antagonist, degarelix, to two widely and currently used GnRH superagonists (D-Trp6-LHRH and leuprolide) in an experimental model of prostate adenocarcinoma in both short- and long-term studies. The Dunning R-3327H rat carcinoma transplanted into Copenhagen rats (Block et al., 1977; Claflin et al., 1977; Redding and Schally, 1981) is of dorsolateral prostatic origin, developed spontaneously in an aged animal, has histological and biochemical similarities to the human prostatic carcinoma, and is androgen-dependent (Hierowski et al., 1983; Daehlin and Damber, 1986; Daehlin et al., 1987). The growth of the Dunning tumor can be inhibited by various treatments reported to be effective in the clinic, such as GnRH superagonists, antiandrogens, 5-alphareductase inhibitors, tyrosine kinase inhibitors, and surgical castration (Ichikawa et al., 1988; Pinski et al., 1994; Presnell et al., 1998; George et al., 1999; Tennant et al., 2000).
Blockage of the GnRH receptor by GnRH antagonists produces a fast, profound, and sustained suppression of gonadotrophin release and, therefore, testosterone secretion in human males (Jockenhovel et al., 1988; Salameh et al., 1991; Bagatell et al., 1993, 1995; Klingmuller et al., 1993; Pinski et al., 1994). Consequently, antagonists such as degarelix have been recognized as potential drugs for the management of sex steroid-dependent pathologies, such as prostate cancer.
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Materials and Methods |
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Tumor Preparation. Cryopreserved R-3327H tumor trocar pieces were obtained from Dr. J. T. Isaacs (John Hopkins Oncology Center, Baltimore, MD), and they were kept in liquid nitrogen. Before implantation, the trocar pieces were thawed by immersing the vial in a 37°C water bath, and tumors were washed in RPMI 1640 medium. Surgical operations were performed under isoflurane anesthesia. The hairs from the flank region of rats were shaved, and a skin incision was made. Fresh tumor trocar pieces of R-3327H tumor were serially implanted subcutaneously into the right flank of the rats (one tumor/rat). Before implantation, the mean weight of 10 tumor fragments was 48.5 ± 2.6 mg.
Test Substance. Degarelix [N-acetyl-3-(naphtalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-L-seryl-4-[[[(4S)-2,6-dioxohexahydropyrimidin-4-yl]carbonyl]amino]-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl-D-alaninamide], FE 200486 acetate salt (batch no. 2010-042-01; mol. wt., 1632.3; peptide content, 88.2%; purity, 98.8%) was supplied by Ferring Research Institute (San Diego, CA) as a white powder. It was stored at -20°C. The manipulation of compound was performed under laminar flow conditions. The vehicle of degarelix was 5% mannitol diluted in sterile distilled water. The degarelix solutions were prepared just before administration to animals.
D-Trp6-LHRH acetate (Triptorelin; batch no. 0537085; mol. wt., 1311.5; purity, 89.9%) was obtained from Bachem (Zurich, Switzerland) as a white powder. It was stored at -20°C. The manipulation of compound was performed under laminar flow conditions.
Leuprolide-depot (Enantone; batch no. S306) was supplied by Oncodesign from Takeda (Puteaux, France). The vehicle for leuprolide was composed of cellulose and D-mannitol diluted in distilled water just before administration to rats.
Treatment Doses and Regimens. Treatments started at D0 when the tumor size reached approximately 300 mm3. Before treatment, the mean tumor size of each group at randomization was not statistically different. For the short-term study, D-Trp6-LHRH was administered subcutaneously at 0.5 mg base/kg, daily for 62 days (n = 10). At this dose, D-Trp6-LHRH induced a complete suppression of testosterone after the flare-up period to levels published in the literature (Redding and Schally, 1981, 1990; Schally et al., 1986). Degarelix was administered subcutaneously at 1.0 mg base/kg, monthly (n = 10). The pharmacological profile of degarelix has been described recently (Broqua et al., 2002; Agerso et al., 2003). At this dose, degarelix induced complete and rapid suppression of testosterone. One control group received a monthly subcutaneous injection of 5% mannitol (n = 10), and another control group was castrated and injected subcutaneously with 5% mannitol once a month (n = 10). The blood samples were collected at D0, D1, D2, D3, D4, D5, D6, D7, D10, D14, D21, D28, D35, D42, D49, and D62. For the group treated with D-Trp6-LHRH, blood samples were also taken 2 h after treatment. For the long-term study, leuprolide-depot was administered subcutaneously at 1.5 mg base/kg, every 3 weeks until day 288 (n = 11). At this dose, leuprolide-depot induced a complete suppression of testosterone after the flare-up period to levels published in the literature (Okada et al., 1991). Degarelix was administered subcutaneously at 1.0 mg base/kg, monthly (n = 11) (Broqua et al., 2002; Agerso et al., 2003). One control group received a monthly subcutaneous injection of 5% mannitol (n = 11), and another control group was castrated and injected subcutaneously with 5% mannitol once a month (n = 11). Blood samples were collected at D0, D2, and every month thereafter until the end of the study (D343).
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Castration. A 0.8-cm incision was made transversally in the abdomen, just above the pubis. The anterior abdominal muscles and skin were incised, and the testes were delivered into the surgical field and removed from animals. The incisions were closed separately using Dexon needle and suture thread (reference 58419; Sherwood, Bondoufle, France).
Sacrifice of Animals. The animals were sacrificed under anesthesia with isoflurane by cervical dislocation. The R-3327H tumors, seminal vesicles, prostates, and testes of each rat were removed, cleaned, and weighed. Animals reaching the maximal tumor size defined by the welfare of the animal were sacrificed.
Tumor Volume Determination. The length and width of the tumor were measured once a week with calipers, and the volume of the tumor was estimated by the formula (length x width2)/2.
Statistical Analysis. The statistical tests were performed using StatView software (Abacus Concepts, Berkeley, CA). The following parameters were compared: the plasma testosterone level at each sampling time; the mean body weight change; the weight of tumors, seminal vesicles, testes, and prostates at the end of the experiment; and the tumor volumes on each day of measurement. Statistical analysis of the treatment was performed using an analysis of variance followed by Bonferroni/Dunn multiple comparison procedures or by unpaired t-tests. A p value <0.05 was considered significant.
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Results |
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Effects of Degarelix and D-Trp6-LHRH on Tissues Weights. Testes weights at the end of the study (D62) represent an integrated measure of the pituitary-gonadal axis activity over time. Testes weights was significantly lower (p < 0.01) in rats treated with degarelix (410 ± 40 mg) compared with rats treated with D-Trp6-LHRH (900 ± 120 mg). Control animals showed normal testes weights (2650 ± 250 mg) compared with the two treated groups (Table 1). However, no statistically relevant differences were observed for the weight of the seminal vesicles and prostates of the animals treated with D-Trp6-LHRH or degarelix (40 ± 10 and 30 ± 20 mg, respectively) (Table 1). Prostates from castrated animals were too small to be weighted accurately.
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Effects of Degarelix, D-Trp6-LHRH, and Surgical Castration on Tumor Volume. Degarelix and surgical castration produced an immediate suppression of tumor growth that lasted throughout the study period (Fig. 2). Tumor volumes in rats treated with degarelix were significantly smaller than those in control rats at D21. This difference lasted until the end of the study at D62. For the D-Trp6-LHRH group, there is no apparent suppression of the tumor growth until D38 compared with control animals. A significant difference (p < 0.01) between D-Trp6-LHRH-treated rats and controls occurred at D49, and it lasted until the end of the study at D62 (Fig. 2; Table 1).
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Effects of Degarelix, D-Trp6-LHRH, and Surgical Castration on Tumor Weight. At the end of the study (D62), tumors were excised and weighed. Tumors in the degarelix-treated and surgically castrated groups had similar weights (310 ± 150 and 370 ± 120 mg, respectively). Tumors in the degarelix-treated group were significantly smaller (p < 0.01) than tumors in the D-Trp6-LHRH-treated group (370 ± 120 versus 1340 ± 750 mg) (Table 1).
Long-Term Effects of Degarelix, Leuprolide-Depot, and Surgical Castration on the Growth of the Dunning R-3327H
Effects of Degarelix, Surgical Castration, and Leuprolide-Depot on Plasma Testosterone Levels. Degarelix suppressed testosterone to castration levels within 2 days of treatment initiation, and it maintained castration levels throughout the course of the study. Onset of testosterone suppression by leuprolide-depot was delayed after the flare-up period, with castration levels achieved within a month. Thereafter, testosterone remained suppressed until treatment was stopped. Control animals stayed within normal range (
2 ng/ml) throughout the study (Fig. 3). Data from animals of the control and leuprolide-depot groups were discarded after 223 days because of the smaller group size (animals reaching the maximal size of the tumor were sacrificed). However, data from castrated and degarelix-treated groups were continued until the end of the study (D343).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Bahk et al., 1998; Limonta et al., 1999). The Dunning tumor expresses GnRH receptors; it is therefore possible that long-term exposure to leuprolide may stimulate proliferative pathways or promote adaptation to androgen-deprivation. Second, it has been suggested that escape from androgen deprivation occurs when the tumor has adapted to low levels of androgens. In tumors escaping from androgen deprivation, androgen receptors and downstream pathways for control of androgen-dependent gene expression are still functional. Escape from androgen deprivation could result from mutation of androgen receptors leading to ligand-independent activation, or from supersensitivity of the androgen receptors and/or activation of alternative transcription factors. In that situation even very low levels of androgens will be sufficient to maintain tumor survival and expansion. In conclusion, degarelix is a new GnRH antagonist immediately blocking GnRH receptors in the pituitary, resulting in a fast and sustained suppression of gonadotrophin secretion and inducing a sustained inhibition of tumor growth at least comparable with surgical castration. The fast cessation of testosterone production by degarelix is clearly advantageous, allowing an immediate inhibition of tumor growth and avoiding other side effects of the flare. Such a rapid antitumor response cannot be achieved by a GnRH superagonist. In the long-term studies, superiority of degarelix over a GnRH agonist is demonstrated; escape to androgen independence occurred sooner in animals treated with the GnRH superagonist leuprolide. These data provide a convincing profile of degarelix (GnRH antagonist) as a more effective GnRH blocker than the superagonists to inhibit the growth of the Dunning tumor, possibly due a better short-term and long-term testosterone control, and they provide a convincing profile of degarelix as a potential candidate for the clinical management of sex steroid-dependent pathologies where long-term chemical castration is required.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: GnRH, gonadotropin-releasing hormone; LHRH, luteinizing hormone-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; D, day.
Address correspondence to: Dr. Marc Princivalle, Ferring Research Ltd., Chilworth Science Park, 1 Venture Rd., Southampton SO16 7NP, UK. E-mail: marc.princivalle{at}ferring.com
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