Preclinical studies of treosulfan demonstrate potent activity in Ewing’s sarcoma

Werner, Sebastian; Mendoza, Arnulfo; Hilger, Ralf A.; Erlacher, Miriam; Reichardt, Wilfried; Lissat, Andrej; Konanz, Claudia; Uhl, Marcus; Niemeyer, Charlotte M.; Khanna, Chand; Kontny, Udo

doi:10.1007/s00280-007-0566-9

Cited by 25 publications

(20 citation statements)

References 37 publications

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“…Consistent with in vivo results (14), rapamycin exposures to the PuMA significantly inhibited metastatic progression at 1 μM. The anticancer activity of treosulfan, a nontargeted cytotoxic chemotherapy, has been shown in vitro and in vivo against a variety of pediatric sarcoma cell lines (15). Significant activity of these agents was confirmed in the PuMA following its addition early or late during the course of metastatic progression.…”

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confidence: 69%

Modeling metastasis biology and therapy in real time in the mouse lung

et al. 2010

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Pulmonary metastasis remains the leading ca use of death for cancer patients. Opportunities to improve treatment outcomes for patients require new methods to study and view the biology of metastatic progression. Here, we describe an ex vivo pulmonary metastasis assay (PuMA) in which the metastatic progression of GFPexpressing cancer cells, from a single cell to the formation of multicellular colonies, in the mouse lung microenvironment was assessed in real time for up to 21 days. The biological validity of this assay was confirmed by its prediction of the in vivo behavior of a variety of high-and low-metastatic human and mouse cancer cell lines and the discrimination of tumor microenvironments in the lung that were most permissive to metastasis. Using this approach, we provide what we believe to be new insights into the importance of tumor cell interactions with the stromal components of the lung microenvironment. Finally, the translational utility of this assay was demonstrated through its use in the evaluation of therapeutics at discrete time points during metastatic progression. We believe that this assay system is uniquely capable of advancing our understanding of both metastasis biology and therapeutic strategies. IntroductionPulmonary metastasis remains a leading cause of death for cancer patients (1, 2). Opportunities to improve outcomes for these patients require a greater understanding of the biology of metastasis. In addition, there is a need to evaluate novel therapeutics, in a timely manner, that specifically target metastases and metastatic progression. Simple in vitro assay systems are not sufficient to model the complex interaction between cancer cells and the surrounding microenvironment that is necessary for metastasis (3). Accordingly, in vivo models of metastasis, largely in mice, have been necessary. For the most part, these models provide end points of metastatic outcome (i.e., yes or no metastasis) and time to late-stage metastatic events.A "black box" exists during which metastatic progression from single cells to gross metastatic lesions at a secondary site occurs. Recent attempts to shed light on this process have included imaging strategies that allow some of the steps of metastatic progression to be followed in vivo (4). However, these approaches often involve sophisticated and expensive imaging techniques that are time consuming and do not easily allow serial assessment of early metastatic progression at secondary sites, particularly in the lung and at the single-cell level. Challenges associated with studying metastasis have resulted in limited opportunities to include the assessment of novel treatment agents against metastatic end points (5). Therefore, an unmet need in the field of cancer research is a simple assay in which the process of metastatic progression at a secondary site can be reproduced and studied over time.

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confidence: 69%

Modeling metastasis biology and therapy in real time in the mouse lung

et al. 2010

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“…1,2 Treosulfan has a broad spectrum of antitumour activity and it is registered for the treatment of ovarian carcinoma. [3][4][5][6] In addition, it was demonstrated both in vivo and in vitro that treosulfan reveals an excellent toxicity against all stem cell lines of the BM and this caused that it was recently administered in high doses within the conditioning regimen prior to allogeneic haematopoietic SCT in patients with haematological malignancies. 7 Despite the clinical use of the oral and i.v.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of high-dose i.v. treosulfan in children undergoing treosulfan-based preparative regimen for allogeneic haematopoietic SCT

Główka

Karaźniewicz−Łada

Grund

et al. 2008

Bone Marrow Transplant

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Pharmacokinetic studies of high-dose treosulfan were carried out in seven paediatric patients (age range: 2-15 years) undergoing treosulfan-based conditioning regimen prior to allogeneic haematopoietic SCT. Treosulfan was administered intravenously in a daily dose of 10, 12 or 14 g/m 2 within 2 h. Five out of seven patients received 12 g/m 2 . The plasma concentrations of treosulfan and its quantity eliminated with urine were determined using a validated HPLC method with refractometric detection. Pharmacokinetic parameters were evaluated following first dose using a two-compartment disposition model. These studies demonstrated a dose-dependent increase of area under the concentration (AUC) and maximum concentrationplasma (C max ), but there was variability of these parameters. Rapid clearance of tresoulfan was observed, especially in 10 and 12 g/m 2 doses. Terminal half-life (t 0.5 ) of treosulfan was in the range of 1.71-2.15 h, but the mean percent of parent drug eliminated with urine was 30%, range 16.3-45.4% of the total dose eliminated during the first 12 h after administration. The results of this study confirmed the linear pharmacokinetics of treosulfan, as used in children. However, variability of pharmacokinetic results observed in children studied demonstrates the need for pharmacokinetic evaluation in each paediatric patient undergoing the treosulfan-based preparative regimen, including those using different doses. This approach could enable further reduction of the risk of early and late organ toxicity related to high-dose treosulfan in paediatric patients.

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“…Treosulfan (L-threitol-1, 4-bis-methanesulfonate) is a water-soluble bifunctional alkylating agent and has been recently shown to be active against ES in vitro and in an orthotopic mouse xenograft-model. 18 …”

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confidence: 97%

Diffusion-Weighted Imaging as Predictor of Therapy Response in an Animal Model of Ewing Sarcoma

Reichardt

Juettner²,

Uhl³

et al. 2009

Investigative Radiology

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Preclinical studies of treosulfan demonstrate potent activity in Ewing’s sarcoma

Abstract: Our results suggest that treosulfan has efficacy against Ewing's sarcoma cells in vitro and in mice. Therefore, controlled trials examining the role of treosulfan in patients with Ewing's sarcoma are warranted.

Cited by 25 publications

References 37 publications

Modeling metastasis biology and therapy in real time in the mouse lung

Modeling metastasis biology and therapy in real time in the mouse lung

Pharmacokinetics of high-dose i.v. treosulfan in children undergoing treosulfan-based preparative regimen for allogeneic haematopoietic SCT

Diffusion-Weighted Imaging as Predictor of Therapy Response in an Animal Model of Ewing Sarcoma

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