Table 2.
Chemical structure of hGnRH-I antagonists (GnRH-ant) and hGnRH-II antagonists (GnRH-ant-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. |
| For evaluating residual gonadotropic function of the pituitary following removal of a pituitary tumor by surgery and/or irradiation. | |||
| Ovulation induction therapy. | |||
| GnRH-ant | |||
| Cetrorelix | Ac-D-2Nal1-D-Phe(4-Cl)2-D-3Pal3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-D-Ala10-NH2 (63, 64). | For the inhibition of premature LH surges in women undergoing controlled ovarian stimulation. | Information not available. |
| EXAMPLES OF USES REPORTED IN CANCER MODELS In N-nitrosobis (2-oxopropyl) amine induced ductal pancreatic cancer in female Syryan golden hamsters, cetrorelix with somatostatin analogs resulted in market reduction of tumor pancreas weight and increased of apoptosis (65). In rats bearing Dunning R3327H transplantable prostate carcinoma, therapy with microgranules of BF-75 significantly decreased tumor growth (66). Cetrorelix directly inhibit growth of mammary tumor cells [MCF-7 and MCF7 MIII (64, 67)]. In dimethylbenzathracene induced mammary carcinoma in female Sprague Dawley rats, cetrorelix was effective in reducing tumor mass (68). Cetrorelix has significantly stronger antiproliferative effects on human endometrial (HEC-1A and Ishikawa) and ovarian cancer (EFO-21, OVCAR-3, SK-OV-3) cells than Triptorelin (69). In patients with ovarian or mullerian carcinoma resistant to platinum chemotherapy treated with cetrorelix, partial remission and disease stabilization was observed (70). In mouse pheochromocytoma cells and mouse tumor tissue-derived cell line, cetrorelix showed significant anti-tumor effects, leading to reduction in cell viability (71). |
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| hGnRH-II | Pyro-Glu1-His2-Trp3-Ser4-His5-Gly6-Trp7-Tyr8-Pro9-Gly10-NH2 (58). | Information not available. | Information not available. |
| GnRH-ant-II | |||
| Triptorelix-1 | Ac-D2Nal1-D-4Cpa2-D-3Pal3-Ser4-Tyr5-D-Cit6-Trp7-Tyr8-Pro9-D-Ala10-NH2 (72). | Information not available. | Information not available. |
| EXAMPLES OF USES REPORTED IN CANCER MODELS Triptorelix induced growth inhibition of PC3 prostate cancer cells in vitro and inhibited growth of PC3 cells xenografted into nude mice (72, 73). |
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| SN09-2 | Ac-D2Nal1-D-Phe(4-Cl)2-D-3Pal3-Ser4-Phe5-D-Lys6-Trp7-Tyr8-Arg9-D-Ala10-NH2 (72). | SN09-2 reduced the growth and increased apoptosis of PC3 prostate cancer cells and was associated with decreased membrane potential and mitochondrial dysfunction (72). | |
| [Ac-D2Nal1, D-4Cpa2, D-3Pal3,6, Leu8, D-Ala10]-GnRH-II | Ac-D2Nal1-D-4Cpa2- D-3Pal3-Ser4-His5-D-3Pal6-Trp7-Leu8-Pro9-D-Ala10-NH2 (74, 75). | [Ac-D2Nal1, D-4Cpa2, D-3Pal3,6, Leu8, D-Ala10]-GnRH-II induce apoptosis in human endometrial (HEC-1A, HEC-1B and Ishikawa), ovarian (OVCAR-3 and EFO-21) and breast cancer cells (MCF-7 and T47-D) (74, 75). | |
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. Ac; acetyl group. D-Nal; D-naphthyIalanyl. D-Phe(4-Cl) or D-4CPa; 4-Chloro-D-phenylalanine. D-3Pal; 3-D-pyridylalanine. D-Cit; D-citrulline. D-Lys; D-lysine. D-Ala; D-alanine. Underlined amino acids; L-amino acids changed with respect to the parent peptide; FDA: United States Food and Drug Administration (https://www.accessdata.fda.gov/scripts/cder/daf/); DRUGBANK: https://www.drugbank.ca.