Therapeutic Responses to Two New SN-38 Derivatives in Colorectal Cancer Patient-Derived Xenografts and Respective 3D In Vitro Cultures

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dc.contributor.authorUnrug-Bielawska, Katarzyna
dc.contributor.authorEarnshaw, David
dc.contributor.authorCybulska-Lubak, Magdalena
dc.contributor.authorKaniuga, Ewelina
dc.contributor.authorSandowska-Markiewicz, Zuzanna
dc.contributor.authorStatkiewicz, Małgorzata
dc.contributor.authorRumienczyk, Izabela
dc.contributor.authorDąbrowska, Michalina
dc.contributor.authorKocik-Krol, Justyna
dc.contributor.authorKlimkiewicz, Krzysztof
dc.contributor.authorUrbanowicz, Magdalena
dc.contributor.authorNaumczuk, Beata
dc.contributor.authorKozerski, Lech
dc.contributor.authorKrzykawski, Marcin
dc.contributor.authorMikula, Michał
dc.contributor.authorOstrowski, Jerzy
dc.contributor.organizationDepartment of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology
dc.contributor.organizationReal Research Sp. z.o.o., Kraków
dc.contributor.organizationNational Medicines Institute
dc.contributor.organizationInstitute of Organic Chemistry, Polish Academy of Sciences
dc.contributor.organizationDepartment of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education
dc.date.accessioned2024-10-08T13:29:25Z
dc.date.available2024-10-08T13:29:25Z
dc.date.issued2024
dc.description.abstractBackground/Aim: SN-38, an active metabolite of irinotecan, exhibits toxicity to all proliferating cells, causing dose-limiting and potentially life-threatening side effects. Newly established water-soluble derivatives of SN-38, 7-ethyl-9-(N-morpholinyl)methyl-10-hydroxycamptothecin (BN-MOA) and 7-ethyl-9-(N-methylamino)methyl-10-hydroxycamptothecin (BN-NMe), exhibit a unique mechanism of spontaneous alkylation of aromatic bases in DNA and show greater in vitro activity on cancer cell lines than SN-38. The aim of this study was to compare the therapeutic responses to irinotecan, BN-MOA and BN-NMe in vivo and in vitro in 3D cultures using colorectal cancer (CRC) patient derived xenografts (PDX). Materials and Methods: Seven established PDX tissues were subcutaneously grown on the flanks of NSG or NSG-SGM3 mice and tumor diameters were measured with a caliper. Compounds were administrated intraperitoneally at 40 mg/kg every five days. 3D PDX cultures were performed on 96-well LifeGel plates and cell viability was determined with the CellTiter Glo 3D reagent. Results: Treatment with irinotecan significantly delayed or stopped the growth of 5 out of 7 PDXs, with a greater level of inhibition from BN-MOA compared to irinotecan and BN-NMe. In vitro studies exhibited the same trends in SN-38 and BN-NMe but not in BN-MOA. Conclusion: The new SN-38 derivatives, BN-MOA and BN-NMe, showed enhanced therapeutic effects compared to irinotecan in CRC models. BN-MOA demonstrated superior tumor inhibition in vivo, while BN-NMe had similar in vitro activity to SN-38. These findings highlight the potential of BN-MOA for greater antitumor efficacy in vivo, with BN-NMe showing comparable effectiveness to SN-38 in vitro. Future studies should optimize growth models to better predict anticancer drug responses.en
dc.description.sponsorshipPolish National Science Center, grant number 2018/31/B/NZ7/02675
dc.identifier.citationANTICANCER RESEARCH 44: 4219-4224 (2024) ; https://doi.org/10.21873/anticanres.17252
dc.identifier.doi10.21873/anticanres.17252
dc.identifier.issn0250-7005
dc.identifier.issn1791-7530
dc.identifier.urihttps://open.icm.edu.pl/handle/123456789/24920
dc.language.isoen
dc.publisherInternational Institute of Anticancer Research
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Międzynarodoween
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceAnticancer Research
dc.subjectPDXen
dc.subjectirinotecanen
dc.subjectcolorectal canceren
dc.subjectprimary cellsen
dc.subject3D cultureen
dc.titleTherapeutic Responses to Two New SN-38 Derivatives in Colorectal Cancer Patient-Derived Xenografts and Respective 3D In Vitro Culturesen
dc.typearticle
person.identifier.orcidNaumczuk, Beata [0000-0003-3740-8387]
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