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
Inactive orally, rapidly absorbed following subcutaneous administration.
Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine.
44.1 ± 13.6 L [subcutaneous administration of 250 mcg]
121 +/- 42.4 mL/min [prostate cancer with 10.8 mg depot]
The apparent volume of distribution determined after subcutaneous administration of 250 ug aqueous solution of goserelin was 44.1 + or - 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%.
The overall pharmacokinetic profile of goserelin following administration of a Zoladex 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. ... There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals.
The pharmacokinetics of goserelin have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 ug (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing.
Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin.
Goserelin is a synthetic decapeptide analogue of luteinising hormone-releasing hormone (LHRH). For experimental purposes it has been administered subcutaneously as an aqueous solution, but for therapeutic use it is formulated as subcutaneous depots releasing goserelin over periods of 1 (3.6 mg) or 3 (10.8 mg) months. Pharmacokinetic data have been generated using a specific radioimmunoassay. When administered as a solution, goserelin is rapidly absorbed and eliminated from serum with a mean elimination half-life (t1/2beta) of 4.2 hours in males and 2.3 hours in females. The shapes of the observed serum goserelin profiles following administration of the depots are primarily determined by the rate of goserelin release from the biodegradable lactide-glycolide copolymer matrix over periods of 1 or 3 months. There is no clinically relevant accumulation of goserelin during multiple administration of these depots. Goserelin is extensively metabolized prior to excretion. Its pharmacokinetics are unaffected by hepatic impairment, but the mean t1/2beta increases to 12.1 hours in patients with severe renal impairment. This suggests that the total renal clearance (renal metabolism and unchanged drug) is decreased in patients with renal dysfunction. It is unnecessary to adjust the dose or administration interval when the depot formulations are administered to elderly patients or to those with impaired renal or hepatic function. ...

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Metabolism / Metabolites
Hepatic
Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1-7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species.

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Biological Half-Life
4-5 hours
When administered as a solution, goserelin is rapidly absorbed and eliminated from serum with a mean elimination half-life (t1/2beta) of 4.2 hours in males and 2.3 hours in females.
Subjects with impaired renal function (creatinine clearance less than 20 mL/min) had a serum elimination half-life of 12.1 hours compared to 4.2 hours for subjects with normal renal function.

Hepatotoxicity
Goserelin has been associated with mild serum enzyme elevations during therapy in 3% to 5% of patients, but values above 3 times the upper limit of normal are rare, being reported in less than 1% of recipients. The serum enzyme elevations during goserelin therapy have generally been transient and asymptomatic, resolving even with drug continuation and rarely requiring dose modification or discontinuation. Despite use for several decades, goserelin has been linked to only a single, and not entirely convincing, case of clinically apparent liver injury. Routine monitoring of patients for liver test abnormalities is not recommended.
Likelihood score: D (possible, rare cause of clinically apparent liver injury).

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Protein Binding
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.
Goserelin is a synthetic hormone. In men, it stops the production of the hormone testosterone, which may stimulate the growth of cancer cells. In women, goserelin decreases the production of the hormone estradiol (which may stimulate the growth of cancer cells) to levels similar to a postmenopausal state. When the medication is stopped, hormone levels return to normal.
Goserelin is a Gonadotropin Releasing Hormone Receptor Agonist. The mechanism of action of goserelin is as a Gonadotropin Releasing Hormone Receptor Agonist.
Goserelin is a parenterally administered, gonadotropin releasing hormone (GnRH) agonist which causes an inhibition of estrogen and androgen production and is used predominantly to treat prostate cancer. Goserelin has been associated with a modest rate of serum enzyme elevations during therapy, but has not been convincingly linked to instances of clinically apparent acute liver injury.
Goserelin is a synthetic decapeptide analog of luteinizing hormone-releasing hormone (LHRH) with antineoplastic activity. Goserelin binds to and activates pituitary gonadotropin releasing hormone (GnRH) receptors. Prolonged administration of goserelin inhibits the secretion of pituitary gonadotropin, thereby decreasing levels of testosterone (in males) and estradiol (in females). Administration of this agent in a depot formulation may result in the regression of sex hormone-sensitive tumors and a reduction in sex organ size and function. (NCI04)
A synthetic long-acting agonist of GONADOTROPIN-RELEASING HORMONE. Goserelin is used in treatments of malignant NEOPLASMS of the prostate, uterine fibromas, and metastatic breast cancer.
See also: Goserelin Acetate (has salt form).

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Drug Indication
Goserelin is indicated for: - Use in combination with flutamide for the management of locally confined carcinoma of the prostate - Palliative treatment of advanced carcinoma of the prostate - The management of endometriosis - Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding - Use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women
FDA Label

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Mechanism of Action
Goserelin is a synthetic decapeptide analogue of LHRH. Goserelin acts as a potent inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. The result is sustained suppression of LH and serum testosterone levels.
Zoladex is a synthetic decapeptide analogue of LHRH. Zoladex acts as a potent inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. Following initial administration, ZOLADEX causes an initial increase in serum-luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone. Chronic administration of Zoladex leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 21 days after initiation of therapy. This leads to accessory sex organ regression. In animal and in in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor. In clinical trials using Zoladex 3.6 mg with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy.

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Therapeutic Uses
Goserelin acetate is used for the palliative treatment of advanced prostate cancer. Therapy with a GnRH agonist (e.g., goserelin) currently is considered one of several first-line options for hormonal therapy in patients with prostate cancer ... .
Goserelin is used for the palliative treatment of endometriosis. The manufacturer states that experience with goserelin in the management of this condition has been limited to women 18 years of age and older who received consecutive therapy ... with the drug for 6 months. Goserelin, like other GnRH analogs, produces a reversible hypoestrogenic state, which is thought to be principally responsible for the beneficial effects observed in endometriosis. A 6-month course of goserelin therapy can provide symptomatic (e.g., pain) relief and a reduction in endometriotic lesions; some degree of improvement has persisted in many patients for at least 6 months following completion of therapy. Substantial improvement of clinical symptoms usually occurs within 4 weeks of initiation of goserelin therapy.
Goserelin is used in the palliative treatment of advanced breast cancer in premenopausal and perimenopausal women. In a multicenter, randomized, controlled clinical trial in women with estrogen- or progesterone-receptor-positive breast cancer, goserelin therapy or oophorectomy was associated with objective response rates (complete or partial responses) of 22-31 or 12-27%, time to treatment failure of 6-6.7 or 4-5.5 months, and median survival time of 33.2 or 33.6 months, respectively. In addition, subjective response, characterized by relief of pain and improved performance status, was reported in 48 or 50% of women receiving goserelin or undergoing surgery, respectively.
Goserelin is used as an endometrial-thinning agent prior to endometrial ablation procedures for the treatment of dysfunctional uterine bleeding. In women with dysfunctional uterine bleeding, administration of goserelin (two doses of goserelin (3.6 mg each) given 4 weeks apart) prior to surgery suppressed endometrial growth, reduced uterine size and endometrial thickness, and facilitated surgical ablation.
For more Therapeutic Uses (Complete) data for GOSERELIN (10 total), please visit the HSDB record page.

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Drug Warnings
May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals. Before initiating goserelin therapy in women, pregnancy must be excluded. Women of childbearing potential should be advised to avoid pregnancy while receiving the drug and use an effective nonhormonal method of contraception during goserelin therapy and continue contraception until the return of menses or for at least 12 weeks following subcutaneous implantation of the last 3.6-mg dose of goserelin. No adequate and well-controlled studies to date in humans. If a patient with endometriosis or undergoing endometrial thinning becomes pregnant during goserelin therapy, the drug should be discontinued and the patient should be advised about potential fetal hazard. In addition, if used during pregnancy (i.e., in women with advanced breast cancer), apprise of potential fetal hazard. Although continuous use of goserelin usually inhibits ovulation and stops menstruation, contraception is not ensured.
As with other GnRH agonists, worsening (flare) of signs and/or symptoms (e.g., increased bone pain) of prostate or breast cancer and/or development of new manifestations occasionally have occurred during the initial weeks of therapy with goserelin. Development of these effects apparently results from goserelin-induced transient increases in serum testosterone (in men) or estrogen (in women) concentrations during the initial weeks of therapy. Concomitant therapy with an antiandrogen (e.g., bicalutamide, flutamide, nilutamide) 1 week before and during the first few weeks of goserelin therapy has been used to minimize the development of disease flare in men with prostate cancer.
Cases of spinal cord compression and/or ureteral obstruction have been reported in men with prostate cancer receiving GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases, an immediate orchiectomy should be considered. Goserelin should be administered with caution to patients at particular risk of developing spinal cord compression or ureteral obstruction and these patients should be observed closely during the first month of therapy. Patients with spinal cord compression or ureteral obstruction should receive appropriate treatment for these conditions prior to initiating therapy with goserelin.
Since goserelin exerts pharmacologic effects on the uterus and cervix and may cause an increase in cervical resistance, cervical dilation should be performed carefully in patients undergoing endometrial ablation following use of goserelin as an endometrial thinning agent.
For more Drug Warnings (Complete) data for GOSERELIN (18 total), please visit the HSDB record page.

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Pharmacodynamics
The pharmacokinetics of goserelin have been determined in both male and female healthy volunteers and patients. In these studies, goserelin was administered as a single 250µg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route.

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.)