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dc.contributor.authorZerp, Shuraila F
dc.contributor.authorStoter, T. R
dc.contributor.authorHoebers, Frank J P
dc.contributor.authorvan den Brekel, Michiel W M
dc.contributor.authorDubbelman, Ria
dc.contributor.authorKuipers, Gitta K
dc.contributor.authorLafleur, M. V M
dc.contributor.authorSlotman, Ben J
dc.contributor.authorVerheij, Marcel
dc.date.accessioned2015-09-01T17:00:36Z
dc.date.available2015-09-01T17:00:36Z
dc.date.issued2015-07-30
dc.identifier.citationRadiation Oncology. 2015 Jul 30;10(1):158
dc.identifier.urihttp://dx.doi.org/10.1186/s13014-015-0474-9
dc.identifier.urihttp://hdl.handle.net/10724/31703
dc.description.abstractAbstract Background Pro-survival Bcl-2 family members can promote cancer development and contribute to treatment resistance. Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. Inhibition of anti-apoptotic Bcl-2 family members therefore represents an appealing strategy to overcome resistance to anti-cancer therapies. The aim of this study was to evaluate combined effects of radiation and the pan-Bcl-2 inhibitor AT-101 in HNSCC in vitro. In addition, we determined human plasma levels of AT-101 obtained from a phase I/II trial, and compared these with the effective in vitro concentrations to substantiate therapeutic opportunities. Methods We examined the effect of AT-101, radiation and the combination on apoptosis induction and clonogenic survival in two HNSCC cell lines that express the target proteins. Apoptosis was assessed by bis-benzimide staining to detect morphological nuclear changes and/or by propidium iodide staining and flow-cytometry analysis to quantify sub-diploid apoptotic nuclei. The type of interaction between AT-101 and radiation was evaluated by calculating the Combination Index (CI) and by performing isobolographic analysis. For the pharmacokinetic analysis, plasma AT-101 levels were measured by HPLC in blood samples collected from patients enrolled in our clinical phase I/II study. These patients with locally advanced HNSCC were treated with standard cisplatin-based chemoradiotherapy and received dose-escalating oral AT-101 in a 2-weeks daily schedule every 3 weeks. Results In vitro results showed that AT-101 enhances radiation-induced apoptosis with CI’s below 1.0, indicating synergy. This effect was sequence-dependent. Clonogenic survival assays demonstrated a radiosensitizing effect with a DEF37 of 1.3 at sub-apoptotic concentrations of AT-101. Pharmacokinetic analysis of patient blood samples taken between 30 min and 24 h after intake of AT-101 showed a dose-dependent increase in plasma concentration with peak levels up to 300–700 ng/ml between 1.5 and 2.5 h after intake. Conclusion AT-101 is a competent enhancer of radiation-induced apoptosis in HNSCC in vitro. In addition, in vitro radiosensitization was observed at clinically attainable plasma levels. These finding support further evaluation of the combination of AT-101 with radiation in Bcl-2-overexpressing tumors.
dc.titleTargeting anti-apoptotic Bcl-2 by AT-101 to increase radiation efficacy: data from in vitro and clinical pharmacokinetic studies in head and neck cancer
dc.typeJournal Article
dc.date.updated2015-07-29T18:16:18Z
dc.language.rfc3066en
dc.rights.holderZerp et al.


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