Antitumor Activity of Imidazothioxanthones in Murine and Human Tumor Models In Vitro and In Vivo

dc.contributor.author	Βαρβαρέσου, Αθανασία	el
dc.contributor.author	Ιακώβου, Κρίτων	el
dc.contributor.author	Γκίκας, Ευάγγελος	el
dc.contributor.author	Fichtner, Iduna	en
dc.contributor.author	Fiebig, Heinz - Herbert	en
dc.date.accessioned	2015-04-29T15:46:48Z
dc.date.available	2015-04-29T15:46:48Z
dc.date.issued	2015-04-29
dc.identifier.uri	http://hdl.handle.net/11400/9267
dc.rights	Αναφορά Δημιουργού-Μη Εμπορική Χρήση-Όχι Παράγωγα Έργα 3.0 Ηνωμένες Πολιτείες	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/us/	*
dc.source	http://www.ncbi.nlm.nih.gov	en
dc.source	http://ar.iiarjournals.org/content/24/2B/907.full.pdf	en
dc.subject	Καρκίνος
dc.subject	Όγκος
dc.subject	Πειράματα
dc.subject	Χημειοθεραπεία
dc.subject	Cancer
dc.subject	Tumor
dc.subject	Experiments
dc.subject	Chemotherapy
dc.title	Antitumor Activity of Imidazothioxanthones in Murine and Human Tumor Models In Vitro and In Vivo	en
heal.type	journalArticle
heal.classification	Medicine
heal.classification	Oncology
heal.classification	Ιατρική
heal.classification	Ογκολογία
heal.classificationURI	http://id.loc.gov/authorities/subjects/sh00006614
heal.classificationURI	http://id.loc.gov/authorities/subjects/sh85094724
heal.classificationURI	N/A-Ιατρική
heal.classificationURI	N/A-Ογκολογία
heal.contributorName	Double, J. A.	en
heal.contributorName	Kelland, L. R.	en
heal.contributorName	Bibby, M. C.	en
heal.contributorName	Hendriks, H. R.	en
heal.language	en
heal.access	free
heal.recordProvider	Τεχνολογικό Εκπαιδευτικό Ίδρυμα Αθηνών. Σχολή Επαγγελμάτων Υγείας και Πρόνοιας. Τμήμα Αισθητικής και Κοσμητολογίας	el
heal.publicationDate	2004-03
heal.bibliographicCitation	Varvaresou, A., Iakovou, K., Gikas, E., Fichtner, I., Fiebig, H. H. et al. (2004) Antitumor Activity of Imidazothioxanthones in Murine and Human Tumor Models In Vitro and In Vivo. "Anticancer Research" 24 (2 B), p.907-919	en
heal.tableOfContents	A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels of human and murine tumor cell lines in vitro, and the in vivo activity against human and murine solid tumors of the most potent compound, N-[3-(Dimethylamino)propylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10a). In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. MATERIALS AND METHODS: The cytotoxicity of compounds 10a, 11-oxo-N-[2-(pyrrolidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide, 11-oxo-N-[2-(piperidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide and N-[2-(morpholino)ethylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10c-10e) was assessed in human tumor cell lines and xenografts using the sulforhodamine B assay, MTT assay and the clonogenic assay. The human ovarian xenograft, PXN/109TC, two human breast carcinomas, MT-1 and MCF-7, and the murine colon adenocarcinoma, MAC15A were used for the in vivo testing of compound 10a. In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. RESULTS: Two compounds, 10a and 10c, showed cytotoxic activity below 10 mM in the NCI in vitro screen of 60 human tumor cell lines. The IC50 value of compound 10a was 6.8 mM and that of 10c, 8.3 mM. In addition, both compounds possessed differential activity against leukemia, colon and mammary cancer. The activity pattern was confirmed in two further screens using monolayer and clonogenic, assays. In vivo antitumor studies showed that 10a was active against the human mammary carcinoma MT-1 and murine colon cancer MAC15A. Marginal activity was observed in human ovarian cancer model PXN/109T/C and the compound was inactive in human mammary cancer MCF-7. CONCLUSION: The results warrant further in vivo testing of 10a in additional human solid tumor models. The molecular modeling showed that the planarity of the chromophore and the side-chain conformation could assist the insertion of compound 10a between the base pairs of the double helix. On the other hand, docking to the nucleotide sequence GGAATTGCCTCA suggested that the molecule could also act as a minor groove binder.	en
heal.journalName	Anticancer Research	en
heal.journalType	peer-reviewed
heal.fullTextAvailability	true