Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients
PurposeIn the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects.Metho...
Gespeichert in:
| Hauptverfasser: | , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
13 June 2017
|
| In: |
Cancer chemotherapy and pharmacology
Year: 2017, Jahrgang: 80, Heft: 2, Pages: 433-439 |
| ISSN: | 1432-0843 |
| DOI: | 10.1007/s00280-017-3357-y |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1007/s00280-017-3357-y Verlag, Volltext: https://link-springer-com.ezproxy.medma.uni-heidelberg.de/article/10.1007/s00280-017-3357-y 
|
| Verfasserangaben: | Jürgen Burhenne, Lu Liu, Christoph E. Heilig, Andreas D. Meid, Margarete Leisen, Thomas Schmitt, Bernd Kasper, Walter E. Haefeli, Gerd Mikus, Gerlinde Egerer |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1577915720 | ||
| 003 | DE-627 | ||
| 005 | 20230426230740.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 180725s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00280-017-3357-y |2 doi | |
| 035 | |a (DE-627)1577915720 | ||
| 035 | |a (DE-576)507915720 | ||
| 035 | |a (DE-599)BSZ507915720 | ||
| 035 | |a (OCoLC)1341014235 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Burhenne, Jürgen |d 1963- |e VerfasserIn |0 (DE-588)1034228889 |0 (DE-627)745126987 |0 (DE-576)381858197 |4 aut | |
| 245 | 1 | 0 | |a Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients |c Jürgen Burhenne, Lu Liu, Christoph E. Heilig, Andreas D. Meid, Margarete Leisen, Thomas Schmitt, Bernd Kasper, Walter E. Haefeli, Gerd Mikus, Gerlinde Egerer |
| 264 | 1 | |c 13 June 2017 | |
| 300 | |a 7 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 25.07.2018 | ||
| 520 | |a PurposeIn the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects.MethodsIn ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs.ResultsPharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary.ConclusionHDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far. | ||
| 700 | 1 | |a Liu, Lu |d 1980- |e VerfasserIn |0 (DE-588)1017021937 |0 (DE-627)672407965 |0 (DE-576)351433899 |4 aut | |
| 700 | 1 | |a Heilig, Christoph E. |d 1981- |e VerfasserIn |0 (DE-588)141951141 |0 (DE-627)632539798 |0 (DE-576)325796440 |4 aut | |
| 700 | 1 | |a Meid, Andreas |d 1981- |e VerfasserIn |0 (DE-588)1076301991 |0 (DE-627)834660377 |0 (DE-576)445184582 |4 aut | |
| 700 | 1 | |a Kasper, Bernd |d 1974- |e VerfasserIn |0 (DE-588)12274764X |0 (DE-627)082130736 |0 (DE-576)29340447X |4 aut | |
| 700 | 1 | |a Haefeli, Walter E. |d 1958- |e VerfasserIn |0 (DE-588)124572359 |0 (DE-627)656806141 |0 (DE-576)340514221 |4 aut | |
| 700 | 1 | |a Mikus, Gerd |e VerfasserIn |0 (DE-588)110903137 |0 (DE-627)691097941 |0 (DE-576)336988710 |4 aut | |
| 700 | 1 | |a Egerer, Gerlinde |e VerfasserIn |0 (DE-588)105502168X |0 (DE-627)792516745 |0 (DE-576)167430882 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer chemotherapy and pharmacology |d Berlin : Springer, 1978 |g 80(2017), 2, Seite 433-439 |h Online-Ressource |w (DE-627)253390435 |w (DE-600)1458488-8 |w (DE-576)072283467 |x 1432-0843 |7 nnas |a Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients |
| 773 | 1 | 8 | |g volume:80 |g year:2017 |g number:2 |g pages:433-439 |g extent:7 |a Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00280-017-3357-y |x Verlag |x Resolving-System |3 Volltext |
| 856 | 4 | 0 | |u https://link-springer-com.ezproxy.medma.uni-heidelberg.de/article/10.1007/s00280-017-3357-y |x Verlag |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20180725 | ||
| 993 | |a Article | ||
| 994 | |a 2017 | ||
| 998 | |g 105502168X |a Egerer, Gerlinde |m 105502168X:Egerer, Gerlinde |d 910000 |d 910100 |e 910000PE105502168X |e 910100PE105502168X |k 0/910000/ |k 1/910000/910100/ |p 10 |y j | ||
| 998 | |g 110903137 |a Mikus, Gerd |m 110903137:Mikus, Gerd |d 910000 |d 910100 |e 910000PM110903137 |e 910100PM110903137 |k 0/910000/ |k 1/910000/910100/ |p 9 | ||
| 998 | |g 124572359 |a Haefeli, Walter E. |m 124572359:Haefeli, Walter E. |d 910000 |d 910100 |e 910000PH124572359 |e 910100PH124572359 |k 0/910000/ |k 1/910000/910100/ |p 8 | ||
| 998 | |g 12274764X |a Kasper, Bernd |m 12274764X:Kasper, Bernd |d 60000 |d 65500 |e 60000PK12274764X |e 65500PK12274764X |k 0/60000/ |k 1/60000/65500/ |p 7 | ||
| 998 | |g 1076301991 |a Meid, Andreas |m 1076301991:Meid, Andreas |d 910000 |d 910100 |e 910000PM1076301991 |e 910100PM1076301991 |k 0/910000/ |k 1/910000/910100/ |p 4 | ||
| 998 | |g 141951141 |a Heilig, Christoph E. |m 141951141:Heilig, Christoph E. |d 910000 |d 910100 |e 910000PH141951141 |e 910100PH141951141 |k 0/910000/ |k 1/910000/910100/ |p 3 | ||
| 998 | |g 1017021937 |a Liu, Lu |m 1017021937:Liu, Lu |d 910000 |d 910100 |e 910000PL1017021937 |e 910100PL1017021937 |k 0/910000/ |k 1/910000/910100/ |p 2 | ||
| 998 | |g 1034228889 |a Burhenne, Jürgen |m 1034228889:Burhenne, Jürgen |d 910000 |d 910100 |e 910000PB1034228889 |e 910100PB1034228889 |k 0/910000/ |k 1/910000/910100/ |p 1 |x j | ||
| 999 | |a KXP-PPN1577915720 |e 3019474337 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"type":{"media":"Online-Ressource","bibl":"article-journal"},"origin":[{"dateIssuedKey":"2017","dateIssuedDisp":"13 June 2017"}],"recId":"1577915720","id":{"doi":["10.1007/s00280-017-3357-y"],"eki":["1577915720"]},"physDesc":[{"extent":"7 S."}],"note":["Gesehen am 25.07.2018"],"relHost":[{"pubHistory":["1.1978 -"],"part":{"text":"80(2017), 2, Seite 433-439","year":"2017","volume":"80","extent":"7","pages":"433-439","issue":"2"},"language":["eng"],"title":[{"title_sort":"Cancer chemotherapy and pharmacology","title":"Cancer chemotherapy and pharmacology","subtitle":"CCP"}],"note":["Gesehen am 02.12.05","Fortsetzung der Druck-Ausgabe","Ungezählte Beil. ab 38.1996: Supplement"],"disp":"Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patientsCancer chemotherapy and pharmacology","physDesc":[{"extent":"Online-Ressource"}],"id":{"issn":["1432-0843"],"zdb":["1458488-8"],"eki":["253390435"]},"recId":"253390435","origin":[{"publisherPlace":"Berlin ; Heidelberg","dateIssuedKey":"1978","dateIssuedDisp":"1978-","publisher":"Springer"}],"titleAlt":[{"title":"CCP"}],"type":{"media":"Online-Ressource","bibl":"periodical"}}],"name":{"displayForm":["Jürgen Burhenne, Lu Liu, Christoph E. Heilig, Andreas D. Meid, Margarete Leisen, Thomas Schmitt, Bernd Kasper, Walter E. Haefeli, Gerd Mikus, Gerlinde Egerer"]},"person":[{"role":"aut","given":"Jürgen","display":"Burhenne, Jürgen","family":"Burhenne"},{"family":"Liu","display":"Liu, Lu","role":"aut","given":"Lu"},{"family":"Heilig","given":"Christoph E.","role":"aut","display":"Heilig, Christoph E."},{"family":"Meid","display":"Meid, Andreas","role":"aut","given":"Andreas"},{"given":"Bernd","role":"aut","display":"Kasper, Bernd","family":"Kasper"},{"family":"Haefeli","given":"Walter E.","role":"aut","display":"Haefeli, Walter E."},{"display":"Mikus, Gerd","role":"aut","given":"Gerd","family":"Mikus"},{"family":"Egerer","display":"Egerer, Gerlinde","role":"aut","given":"Gerlinde"}],"title":[{"title_sort":"Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients","title":"Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma patients"}],"language":["eng"]} | ||
| SRT | |a BURHENNEJUINTRACELLU1320 | ||