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001-es BibID:BIBFORM082393
035-os BibID:(PMID)31717403 (cikkazonosító)5590 (scopus)85074657590 (wos)000502786800072
Első szerző:Murányi József
Cím:Novel Crizotinib-GnRH conjugates revealed the significance of lysosomal trapping in GnRH-based drug delivery systems / József Murányi, Attila Varga, Pál Gyulavári, Kinga Pénzes, Csilla E. Németh, Miklós Csala, Lilla Pethő, Antal Csámpai, Gábor Halmos, István Peták, István Vályi-Nagy
Dátum:2019
ISSN:1661-6596 1422-0067
Megjegyzések:Several promising anti-cancer drug-GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)- or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [d-Lys6]-GnRH-I targeting peptide. Our most prominent crizotinib-GnRH conjugates, the amide-bond-containing [d-Lys6(crizotinib*)]-GnRH-I and the ester-bond-containing [d-Lys6(MJ55*)]-GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib-GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets-the ATP-binding site of RTKs- and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib-GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug-GnRH conjugates.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
GnRH
GnRHR
NSCLC
c-Met
conjugate
crizotinib
endocytosis
galectin
lysosome
permeability
targeted drug delivery
Megjelenés:International Journal of Molecular Sciences. - 20 : 22 (2019), p. 1-23. -
További szerzők:Varga Attila (biokémikus) Gyulavári Pál Pénzes Kinga Németh Csilla Csala Miklós Pethő Lilla Csámpai Antal Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Peták István Vályi-Nagy István
Pályázati támogatás:NVKP_16-1-2016-0005
Egyéb
K-124813
Egyéb
K-128785
Egyéb
GINOP-2.3.2-15-2016-00043
GINOP
Internet cím:DOI
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2.

001-es BibID:BIBFORM082392
035-os BibID:(PMID)31614426 (cikkazonosító)5027 (scopus)85073444152 (wos)000498822800059
Első szerző:Pethő Lilla
Cím:Suitability of GnRH Receptors for Targeted Photodynamic Therapy in Head and Neck Cancers / Lilla Pethő, József Murányi, Kinga Pénzes, Bianka Gurbi, Diána Brauswetter, Gábor Halmos, Gabriella Csík, Gábor Mező
Dátum:2019
ISSN:1661-6596 1422-0067
Megjegyzések:Head and neck squamous cell carcinomas (HNSCC) have a high mortality rate, although several potential therapeutic targets have already been identified. Gonadotropin-releasing hormone receptor (GnRH-R) expression is less studied in head and neck cancers, hence, we investigated the therapeutic relevance of GnRH-R targeting in HNSCC patients. Our results indicate that half of the patient-derived samples showed high GnRH-R expression, which was associated with worse prognosis, making this receptor a promising target for GnRH-based drug delivery. Photodynamic therapy is a clinically approved treatment for HNSCC, and the efficacy and selectivity may be enhanced by the covalent conjugation of the photosensitizer to a GnRH-R targeting peptide. Several native ligands, gonadotropin-releasing hormone (GnRH) isoforms, are known to target GnRH-R effectively. Therefore, different 4Lys(Bu) modified GnRH analogs were designed and conjugated to protoporphyrin IX. The receptor binding potency of the novel conjugates was measured on human pituitary and human prostate cancer cells, indicating only slightly lower GnRH-R affinity than the peptides. The in vitro cell viability inhibition was tested on Detroit-562 human pharyngeal carcinoma cells that express GnRH-R in high levels, and the results showed that all conjugates were more effective than the free protoporphyrin IX.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
GnRH
GnRH-R
conjugate
head and neck cancer
photodynamic therapy
protoporphyrin
targeted drug delivery
Megjelenés:International Journal of Molecular Sciences. - 20 : 20 (2019), p. 1-17. -
További szerzők:Murányi József Pénzes Kinga Gurbi Bianka Brauswetter Diána Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Csík Gabriella Mező Gábor (1959-) (vegyész)
Internet cím:Szerző által megadott URL
DOI
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