In EOC cells, goserelin (1 nM–1 mM; 48–72 hours) stimulates apoptosis [1]. In SKOV3-ip cells, goserelin (100 μM; 24-72 hours) controls the expression of genes linked to human apoptosis [1]. Goserelin (100 μM; 24-72 hours) increases FOXO1 via the PI3K/AKT signaling pathway, which influences the death of EOC cells [1].

The percentage of apoptotic cells in subcutaneous xenograft tumors is markedly increased by goserelin (100 µg; subcutaneous injection; daily; for 19 days) [1].

Apoptosis analysis[1]
Cell Types: SKOV3 cells, SKOV3-ip cells, A2780 cells (human EOC cell line)
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1 mM
Incubation Duration: 48 hrs (hours), 72 hrs (hours)
Experimental Results: Dramatically increased the total apoptosis rate of SKOV3-ip, SKOV3 and A2780 cells.

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Western Blot Analysis[1]
Cell Types: SKOV3 cells, SKOV3-ip cells, A2780 cells (human EOC cell line)
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1 mM
Incubation Duration: 48 Hour and 72 hour
Experimental Results: At 100 μM, the expression of cleaved-caspase-3 and cleaved-PARP increased Dramatically.

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RT-PCR[1]
Cell Types: SKOV3-ip Cell
Tested Concentrations: 100 μM
Incubation Duration: 24 hrs (hours), 48 hrs (hours), 72 hrs (hours)
Experimental Results: Expression of human apoptosis-related genes is regulated

Animal/Disease Models: Fiveweeks old specific pathogen-free (SPF) female nude mice (18-20 g), subcutaneousxenograft tumor model [1]
Doses: 100 µg/mouse
Route of Administration: subcutaneous injection, daily, for 19 days
Experimental Results: Dramatically increased proportion of apoptotic cells in subcutaneousxenograft tumors

Absorption, Distribution and Excretion
Oral administration is ineffective; absorption is rapid after subcutaneous injection. Following subcutaneous injection of radiolabeled goserelin solution, clearance of goserelin is very rapid, primarily via the liver and urine. Over 90% of the subcutaneously injected dose of radiolabeled goserelin solution is excreted in the urine. 44.1 ± 13.6 L [Subcutaneous injection 250 mcg] 121 ± 42.4 mL/min [Prostate cancer, 10.8 mg extended-release] The apparent volume of distribution after subcutaneous injection of 250 μg of goserelin aqueous solution in healthy men was 44.1 ± 13.6 L. The plasma protein binding rate of goserelin was 27%. This study determined the overall pharmacokinetic characteristics of goserelin in prostate cancer patients treated with 10.8 mg Zoladex extended-release formulation. Goserelin exhibits a relatively rapid initial release from its extended-release formulation, reaching peak plasma concentrations 2 hours after administration. From day 4 until the end of the 12-week dosing interval, sustained release of goserelin from the extended-release formulation resulted in relatively stable systemic exposure. …No clinically significant accumulation of goserelin was observed after four doses administered at 12-week intervals. The pharmacokinetics of goserelin have been determined in healthy male volunteers and patients. In healthy men, a single subcutaneous injection of 250 μg (aqueous solution) of radiolabeled goserelin was administered. The radiolabeled drug was rapidly absorbed, reaching peak plasma concentrations 0.5 to 1.0 hours after administration. Following subcutaneous injection of the radiolabeled goserelin solution, clearance of goserelin is very rapid, primarily via the liver and urine. Over 90% of the subcutaneously injected dose of the radiolabeled goserelin solution is excreted in the urine. Approximately 20% of the dose recovered in the urine is unmetabolized goserelin. Goserelin is a synthetic decapeptide analog of luteinizing hormone-releasing hormone (LHRH). In experimental settings, goserelin was administered subcutaneously as an aqueous solution; however, in therapeutic applications, it is formulated as a subcutaneous sustained-release formulation, providing sustained release over 1 month (3.6 mg) or 3 months (10.8 mg). Pharmacokinetic data were obtained using specific radioimmunoassay. When administered as a solution, goserelin is rapidly absorbed and eliminated from serum, with a mean elimination half-life (t1/2β) of 4.2 hours in men and 2.3 hours in women. The serum goserelin concentration profile observed after administration depends primarily on the rate of release from the biodegradable lactate-glycolic acid copolymer matrix over 1 or 3 months. Repeated administration of these sustained-release formulations does not lead to clinically relevant accumulation of goserelin. Goserelin undergoes extensive metabolism before excretion. Its pharmacokinetics are not affected by hepatic impairment, but in patients with severe renal impairment, the mean t1/2β is prolonged to 12.1 hours. This indicates a decrease in total renal clearance (renal metabolism and parent drug) in patients with renal insufficiency. No dose or dosing interval adjustment is required for elderly patients or patients with impaired renal or hepatic function. ...

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Metabolism/Metabolites
Hepatic Metabolism
The main clearance mechanism of goserelin is via the hydrolysis of C-terminal amino acids. The main circulating components in serum appear to be fragments 1–7, while the main components in the urine of a healthy male volunteer are fragments 5–10. The metabolite profile produced by the metabolism of goserelin in humans is similar to that of other species, but narrower. All metabolites found in humans are also found in the toxicological species.

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Biological Half-Life
4-5 hours
When goserelin is administered in solution, it is rapidly absorbed and eliminated from serum. The average elimination half-life (t1/2β) is 4.2 hours for men and 2.3 hours for women.
The serum elimination half-life is 12.1 hours in subjects with impaired renal function (creatinine clearance less than 20 mL/min), compared to 4.2 hours in subjects with normal renal function.

Hepatotoxicity
During goserelin treatment, mild serum enzyme elevations occur in 3% to 5% of patients, but elevations exceeding three times the upper limit of normal are rare, with a reported incidence of less than 1%. Serum enzyme elevations during goserelin treatment are usually transient and asymptomatic, resolving spontaneously with continued use, rarely requiring dose adjustment or discontinuation. Although goserelin has been used for decades, only one clinically significant case of liver injury has been associated with this case, and the clinical evidence for this case is not entirely conclusive. Routine liver function tests are not recommended for this patient. Probability score: D (Possibly a rare cause of clinically significant liver injury). Protein binding rate 27.3%

[1]. Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead box O1 through the PI3K/AKT signaling pathway. Oncol Rep. 2018 Mar; 39(3): 1034–1042.

[2]. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015 Mar 5;372(10):923-32.

Goserelin is an organic molecular entity. It is a synthetic hormone. In men, it inhibits testosterone production, which can stimulate cancer cell growth. In women, it reduces estradiol production (a hormone that can stimulate cancer cell growth), bringing its levels close to postmenopausal levels. Hormone levels return to normal after discontinuation. Goserelin is a gonadotropin-releasing hormone receptor agonist. Its mechanism of action is as a gonadotropin-releasing hormone receptor agonist. Goserelin is a parenteral gonadotropin-releasing hormone (GnRH) agonist that inhibits the production of estrogen and androgens, primarily used to treat prostate cancer. Serum enzyme levels may slightly increase during goserelin treatment, but there is no conclusive evidence linking it to clinically significant cases of acute liver injury. Goserelin is a synthetic luteinizing hormone-releasing hormone (LHRH) decapeptide analog with antitumor activity. Goserelin binds to and activates the pituitary gonadotropin-releasing hormone (GnRH) receptor. Long-term use of goserelin inhibits the secretion of pituitary gonadotropins, thereby reducing testosterone levels in men and estradiol levels in women. Long-acting, sustained-release formulations can cause regression of sex hormone-sensitive tumors and reduce the size and function of sex organs. (NCI04)
A synthetic, long-acting gonadotropin-releasing hormone agonist. Goserelin is used to treat prostate cancer, uterine fibroids, and metastatic breast cancer.
See also: Goserelin acetate (salt form).

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Drug Indications
Goserelin is indicated for: - In combination with flutamide for the treatment of localized prostate cancer - Palliative treatment of advanced prostate cancer - Treatment of endometriosis - Use as an endometrial thinner prior to endometrial ablation for the treatment of dysfunctional uterine bleeding - Palliative treatment of advanced breast cancer in premenopausal and perimenopausal women
FDA Label

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Mechanism of Action
Goserelin is a synthetic decapeptide analog of gonadotropin-releasing hormone (LHRH). When administered in a biodegradable formulation, goserelin effectively inhibits the secretion of pituitary gonadotropins. The result is sustained suppression of luteinizing hormone (LH) and serum testosterone levels.
Goserelin (Zoladex) is a synthetic decapeptide analog of gonadotropin-releasing hormone (LHRH). When administered in a biodegradable formulation, goserelin effectively inhibits the secretion of pituitary gonadotropins. Following initial administration, goserelin causes an initial increase in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, followed by an increase in serum testosterone levels. Long-term use of goserelin sustains suppression of pituitary gonadotropins; therefore, approximately 21 days after starting treatment, serum testosterone levels drop to levels seen in normally castrated men. This leads to the degeneration of accessory sex organs. In animal and in vitro studies, administration of goserelin resulted in regression or inhibition of growth of hormone-sensitive dimethylbenzanthracene (DMBA)-induced mammary tumors and Dunning R3327 prostate tumors in rats. Clinical trials using 3.6 mg of goserelin (Zoladex) with a follow-up period exceeding two years showed that serum testosterone levels remained at castration levels throughout the treatment period.

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Therapeutic Use
Goserelin acetate is used for palliative treatment of advanced prostate cancer.
Currently, treatment with gonadotropin-releasing hormone (GnRH) agonists (such as goserelin) is considered one of the first-line options for hormone therapy in prostate cancer patients…
Goserelin is used for palliative treatment of endometriosis. The manufacturer notes that experience with goserelin in treating this disease is limited to women aged 18 years and older who have received continuous 6 months of treatment. Like other GnRH analogues, goserelin produces a reversible hypoestrogenic state, which is considered the main reason for its beneficial effects observed in endometriosis. Six months of goserelin treatment can relieve symptoms (such as pain) and reduce endometriotic lesions; many patients maintain some degree of improvement for at least 6 months after completing treatment. Clinical symptoms usually improve significantly within 4 weeks of starting goserelin treatment.
Goserelin is used for palliative treatment of advanced breast cancer in premenopausal and perimenopausal women. In a multicenter, randomized, controlled clinical trial of estrogen receptor or progesterone receptor-positive breast cancer, the objective response rates (complete or partial response) of goserelin treatment or oophorectomy were 22-31% and 12-27%, respectively; the time to treatment failure was 6-6.7 months and 4-5.5 months, respectively; and the median survival was 33.2 months and 33.6 months, respectively. Furthermore, 48% and 50% of women receiving goserelin treatment or undergoing surgery reported subjective efficacy, including pain relief and improved physical condition. Goserelin is used as a preoperative endometrial thinning agent for the treatment of dysfunctional uterine bleeding. For patients with dysfunctional uterine bleeding, preoperative administration of goserelin (two doses of 3.6 mg each, administered 4 weeks apart) inhibits endometrial growth, reduces uterine volume and endometrial thickness, and facilitates surgical ablation. For more complete data on the therapeutic uses of goserelin (out of 10), please visit the HSDB records page.

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Drug Warnings
May cause harm to the fetus; animal studies have demonstrated embryotoxicity and fetal toxicity. Pregnancy must be ruled out before initiating goserelin treatment in a woman. Women of childbearing age should be advised to avoid pregnancy during goserelin treatment and should use an effective non-hormonal contraceptive method during treatment until menstruation resumes or at least 12 weeks after the last subcutaneous injection of 3.6 mg goserelin. There are currently no adequate and well-controlled human studies. If a patient with endometriosis or undergoing treatment for thinning of the endometrium becomes pregnant during goserelin treatment, the medication should be discontinued and the patient informed of the potential fetal risk. Additionally, if used during pregnancy (e.g., in patients with advanced breast cancer), the patient should also be informed of the potential fetal risk. While continued use of goserelin usually suppresses ovulation and stops menstruation, it does not guarantee contraceptive effectiveness. As with other gonadotropin-releasing hormone agonists, occasional exacerbations of signs and/or symptoms of prostate or breast cancer (recurrence) (e.g., increased bone pain) and/or the appearance of new symptoms may occur during the first few weeks of goserelin treatment. These adverse reactions are clearly due to a transient increase in serum testosterone (male) or estrogen (female) levels caused by goserelin during the initial weeks of treatment. Anti-androgen drugs (e.g., bicalutamide, flutamide, nilumid) are usually used concurrently in the week preceding goserelin treatment and during the first few weeks of treatment to reduce the risk of recurrence in prostate cancer patients. There have been case reports of spinal cord compression and/or ureteral obstruction in prostate cancer patients receiving gonadotropin-releasing hormone agonist treatment. If spinal cord compression or renal impairment occurs, standard treatment measures should be initiated immediately; in extreme cases, immediate orchiectomy should be considered. Goserelin should be used with caution in patients at risk of spinal cord compression or ureteral obstruction, and these patients should be closely monitored during the first month of treatment. Patients with spinal cord compression or ureteral obstruction should receive appropriate treatment for these conditions before initiating treatment with goserelin. Because goserelin has pharmacological effects on the uterus and cervix and may cause increased cervical resistance, cervical dilation should be performed with caution in patients undergoing endometrial ablation after using goserelin as an endometrial thinner. For more complete data on drug warnings for goserelin (18 in total), please visit the HSDB record page. Pharmacodynamics: The pharmacokinetics of goserelin have been determined in healthy male and female volunteers and patients. In these studies, goserelin was administered as a single 250 µg (aqueous solution) dose and as a single or multiple subcutaneous injection of 3.6 mg.

C₅₉H₈₄N₁₈O₁₄

1269.41

1268.641

65807-02-5

Goserelin acetate;145781-92-6

5311128

Typically exists as solid at room temperature

1.5±0.1 g/cm3

1.692

-0.95

17

16

32

91

2560

9

O=C(N[C@H](C(N[C@@H](CC1=CC=C(O)C=C1)C(N[C@H](COC(C)(C)C)C(N[C@@H](CC(C)C)C(N[C@@H](CCCNC(N)=N)C(N2CCC[C@H]2C(NNC(N)=O)=O)=O)=O)=O)=O)=O)CO)[C@@H](NC([C@H](CC3=CN=CN3)NC([C@@H](N4)CCC4=O)=O)=O)CC5=CNC6=C5C=CC=C6

BLCLNMBMMGCOAS-URPVMXJPSA-N

InChI=1S/C59H84N18O14/c1-31(2)22-40(49(82)68-39(12-8-20-64-57(60)61)56(89)77-21-9-13-46(77)55(88)75-76-58(62)90)69-54(87)45(29-91-59(3,4)5)74-50(83)41(23-32-14-16-35(79)17-15-32)70-53(86)44(28-78)73-51(84)42(24-33-26-65-37-11-7-6-10-36(33)37)71-52(85)43(25-34-27-63-30-66-34)72-48(81)38-18-19-47(80)67-38/h6-7,10-11,14-17,26-27,30-31,38-46,65,78-79H,8-9,12-13,18-25,28-29H2,1-5H3,(H,63,66)(H,67,80)(H,68,82)(H,69,87)(H,70,86)(H,71,85)(H,72,81)(H,73,84)(H,74,83)(H,75,88)(H4,60,61,64)(H3,62,76,90)/t38-,39-,40-,41-,42-,43-,44-,45+,46-/m0/s1

(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide

ICI 118630Zoladex. ICI-118630 ICI118630 Goserelin Acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)