Latest documents http://publikationen.ub.uni-frankfurt.de/index/index/ Fri, 02 Aug 2013 09:55:16 +0100 Fri, 02 Aug 2013 09:55:16 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27917 The anti-epileptic drug valproic acid is also under trial as an anti-cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti-neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA-derivatives (ACS2, ACS33) on pre-clinical prostate cancer models. PC3 and DU-145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up-regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU-145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti-tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer. Steffen A. Wedel; Anna Sparatore; Piero Del Soldato; Salah-Eddin Al-Batran; Akin Atmaca; Eva Jüngel; Lukasz Hudak; Dietger Jonas; Roman A. Blaheta article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27917 Fri, 08 Feb 2013 09:55:16 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/1036 Following publication of the data presented by von Minckwitz and colleagues [1] it has been brought to our attention that some patients should be scored differently. Stable disease was seen in three of the eighteen patients instead of two of the eighteen patients: one patient with transitional cell carcinoma treated at 4 micro g/kg scFv(FRP5)-ETA per day, and two breast cancer patients treated at 4 and 12.5 micro g/kg scFv(FRP5)-ETA per day. Disease progression occured in 9 of the eighteen patients evaluated (see corrected Table 2 overleaf). This does not affect the conclusions of our study. In addition we would like to correct the following errors: patient IDs for patients U01 and U02 in the original Table 2 were interchanged. In addition, patient N03 had a grade 3 elevation of gamma-glutamyl transferase, and not grade 2 (see corrected Table 2 overleaf). http://publikationen.ub.uni-frankfurt.de/volltexte/2005/1156/ Gunter von Minckwitz; Sebastian Harder; Sascha Hövelmann; Elke Jäger; Salah-Eddin Al-Batran; Sibylle Loibl; Akin Atmaca; Christian Cimpoiasu; Antje Neumann; Aklil Abera; Alexander Knuth; Manfred Kaufmann; Dirk Jäger; Alexander B. Maurer; Winfried S. Wels article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/1036 Tue, 22 May 2007 15:26:12 +0200 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/4330 Introduction: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients. Methods: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks. Results: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients. Conclusion: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development. Gunter von Minckwitz; Sebastian Harder; Sascha Hövelmann; Elke Jäger; Salah-Eddin Al-Batran; Sibylle Loibl; Akin Atmaca; Christian Cimpoiasu; Antje Neumann; Aklil Abera; Alexander Knuth; Manfred Kaufmann; Dirk Jäger; Alexander B. Maurer; Winfried S. Wels article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/4330 Wed, 22 Jun 2005 14:04:43 +0200