Table 1.
Chemical structure of hGnRH-I agonists (GnRHa) and hGnRH-II agonists (GnRHa-II) evaluated against breast cancer.
| Sequence | Main clinical indication (drugbank and FDA) | Clinical use in breast cancer | |
|---|---|---|---|
| hGnRH-I (Gonadorelin) | Pyro-Glu1-His2-Trp3-Ser4-Tyr5- Gly6-Leu7-Arg8-Pro9-Gly10-NH2 (19). | For evaluating the functional capacity and response of the gonadotropes of the anterior pituitary. | Information not available, only for GnRHa. |
| For evaluating residual gonadotropic function of the pituitary following removal of a pituitary tumor by surgery and/or irradiation. | |||
| Ovulation induction therapy. | |||
| GnRHa | |||
| Triptorelin | Pyro-Glu1-His2-Trp3-Ser4-Tyr5-D-Trp6-Leu7-Arg8-Pro9-Gly10-NH2 (20–24). | Palliative treatment of advanced prostate cancer. | In premenopausal women with early BC letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen with triptorelin (25). |
| In healthy premenopausal women coadministration of triptorelin and exemestane resulted in greater estrogen suppression than when triptorelin was given alone (26). | |||
| In premenopausal women with HR+ early BC, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence (24). | |||
| Controlled ovarian hyperstimulation therapy. | In premenopausal women with BC, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone, was associated with higher long-term probability of ovarian function recovery, however there was no significant difference in DFS (27). | ||
| In premenopausal women with BC, treatment with exemestane plus triptorelin had estradiol levels consistent with levels reported in postmenopausal women on aromatase inhibitors (23). | |||
| In premenopausal women who received adjuvant chemotherapy for HR+, HER2 negative (HER2-) BC, neither detrimental, nor beneficial effect of concurrent administration OFS was detected (28). | |||
| In premenopausal women with stage cT2 to 4b, any N, M0, HR+, and HER2- BC receiving letrozole neoadjuvant, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin (29). | |||
| In premenopausal women with early BC undergoing OFS with triptorelin, the treatment with letrozole and zolendronic acid, improves DFS (30). | |||
| Goserelin | Pyro-Glu1-His2-Trp3-Ser4-Tyr5 D-Ser(But)6-Leu7-Arg8-Pro9-Aza-Gly10-NH2 (31–40). | In combination with flutamide for management of locally confined carcinoma prostate. | In pre y perimenopausal women with metastatic BC, goserelin produced objective response rates and duration of remission at least comparable to those seen following oophorectomy (41). |
| Palliative treatment of advanced carcinoma prostate. | In premenopausal women with early BC, the addition of goserelin to ajuvant chemotherapy was associated with more benefit in DFS and overall survival rates (42). | ||
| The management of endometriosis. | In premenopausal women with HR+ BC, OFS with goserelin plus tamoxifen compared with tamoxifen only provided more benefit in DFS (43). | ||
| In premenopausal women with prior endocrine-resistant HR+, HER2- advanced BC, palbociclib combined with fulvestrant, and goserelin was an effective treatment to extend DFS (44). | |||
| Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding. | In premenopausal women at ≥30% lifetime risk breast cancer, OFS with goserelin is a potential regimen for BC risk reduction (45). | ||
| In premenopausal women with HR+, HER2-, tamoxifen-pretreated metastatic BC, fulvestrant plus goserelin provides a new option for the treatment (46). | |||
| Palliative treatment of advanced BC in pre- and perimenopausal women. | In premenopausal o perimenopausal women with advanced HR+, HER2- BC, overall survival was longer with a CDK4/6 inhibitor plus endocrine therapy (including goserelin) than endocrine therapy alone (47, 48). | ||
| Buserelin | Pyro-Glu1-His2-Trp3-Ser4-Tyr5-D-Ser(But)6-Leu7-Arg8-Pro-NHET9 (49–53). | May be used in the treatment of HR+ cancers such as prostate cancer o BC. | In premenopausal women with metastatic BC, buserelin was associated with objective remission and stable disease (54, 55). |
| May be used in estrogen-dependent conditions (such as endometriosis or uterine fibroids). | In premenopausal women with BC, buserelin plus cytostatics more effectively caused ovarian ablation than cytostatic treatment alone (56). | ||
| May be used in assisted reproduction. | In premenopausal women with advanced BC, the effect of cyclophosphamide, doxorubicin and fluoruracil plus buserelin showed a high response rate (57). | ||
| In premenopausal women with BC, combining OFS with buserelian and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate, more DFS and longer overall survival (51). | |||
| hGnRH-II | Pyro-Glu1-His2-Trp3-Ser4-His5- Gly6-Trp7-Tyr8-Pro9-Gly10-NH2 (58). | Information not available. | Information not available. |
| EXAMPLES OF USES REPORTED IN CANCER MODELS hGnRH-II may be involved in the inhibition of endometrial cancer cell growth (HEC-1A) (59). hGnRH-II can promote apoptosis rate and inhibit cell proliferation of estrogen receptor-negative endometrial cancer cells (HEC-1A) in a dose-dependent manner (60). |
|||
| GnRHa-II | |||
| [D-Lys6]-GnRH-II | Pyro-Glu1-His2-Trp3-Ser4-His5-D-Lys 6-Trp7-Tyr8-Pro9-Gly10-NH2 (21). | Information not available. | Information not available. |
| EXAMPLES OF USES REPORTED IN CANCER MODELS [D-Lys6]-GnRH-II has potent antiproliferative effect on SKOV-3 human ovarian cancer cell line (61). Cytotoxic conjugate prepared by the attachment of the chemotherapeutical agent daunorubicin to [D-Lys6]-GnRH-II had significantly higher long-term cytotoxic than cytostatic effects in human breast (MCF-7) and colon (HT-29) cancer cell lines (62). |
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Pyro-Glu; pyroglutamic acid. His; L-histidine. Trp; L-tryptophan. Ser; L-serine. Tyr; L-tyrosine. Gly; L-glycine. Leu; L-leucine. Arg; L-arginine. Pro; L-proline. D-Trp; D-tryptophan. D-Ser(But); D-serine ter-butyl. NHET; N-ethylamide. Aza-Gly; azaglycine (stands for glycine in which the α-CH has been replaced by a nitrogen atom); BC, breast cancer; HR+, hormone receptor positive; DFS, disease free survival; HER2-, HER2 negative; OFS, ovarian function suppression; FDA, United States Food and Drug Administration (https://www.accessdata.fda.gov/scripts/cder/daf/); DRUGBANK: https://www.drugbank.ca.