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Massard C.,Institut Universitaire de France | Soria J.-C.,Institut Universitaire de France | Anthoney D.A.,University of Leeds | Proctor A.,University of Leeds | And 8 more authors.
Cell Cycle | Year: 2011

Background: PHA-793887 is an inhibitor of multiple cyclin-dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887. Results: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. Patients and Methods: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated. Conclusion: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development. © 2011 Landes Bioscience.

Germani M.,Accelera Srl | Del Bene F.,Accelera Srl | Poggesi I.,Janssen Pharmaceutical | Magni P.,University of Pavia | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: Pharmacokinetic-pharmacodynamic (PK-PD) models able to predict the action of anticancer compounds in tumor xenografts have an important impact on drug development. In case of anti-angiogenic compounds, many of the available models show difficulties in their applications, as they are based on a cell kill hypothesis, while these drugs act on the tumor vascularization, without a direct tumor cell kill effect. For this reason, a PK-PD model able to describe the tumor growth modulation following treatment with a cytostatic therapy, as opposed to a cytotoxic treatment, is proposed here. Methods: Untreated tumor growth was described using an exponential growth phase followed by a linear one. The effect of anti-angiogenic compounds was implemented using an inhibitory effect on the growth function. The model was tested on a number of experiments in tumor-bearing mice given the anti-angiogenic drug bevacizumab either alone or in combination with another investigational compound. Nonlinear regression techniques were used for estimating the model parameters. Results: The model successfully captured the tumor growth data following different bevacizumab dosing regimens, allowing to estimate experiment-independent parameters. A combination model was also developed under a 'no-interaction' assumption to assess the effect of the combination of bevacizumab with a target-oriented agent. The observation of a significant difference between model-predicted and observed tumor growth curves was suggestive of the presence of a pharmacological interaction that was further accommodated into the model. Conclusions: This approach can be used for optimizing the design of preclinical experiments. With all the inherent limitations, the estimated experiment-independent model parameters can be used to provide useful indications for the single-agent and combination regimens to be explored in the subsequent development phases. © 2013 Springer-Verlag Berlin Heidelberg.

Repetto-Llamazares A.H.V.,Nordic Nanovector AS | Repetto-Llamazares A.H.V.,University of Oslo | Larsen R.H.,Sciencons Ltd. | Giusti A.M.,Accelera Srl | And 4 more authors.
PLoS ONE | Year: 2014

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA- HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studieswith 177Lu-HH1. Methodology/Principal Findings: Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group. Conclusions/Significance: 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients. © 2014 Repetto-Llamazares et al.

Palmieri C.,University of Queensland | Riccardi E.,Accelera Srl
Journal of Comparative Pathology | Year: 2013

Homeobox genes are known to be examples of the intimate relationship between embryogenesis and tumourigenesis. Specifically, the HOXA13 gene plays a fundamental role in the development of the urogenital tract and external genitalia and in prostate organogenesis. There are no reports on the expression of HOXA13 in normal, hyperplastic or neoplastic canine prostate tissue or in other types of tumours. Six normal, 16 hyperplastic and 12 neoplastic canine prostates were examined microscopically and immunohistochemically with a polyclonal antibody specific for human HOXA13. An immunohistochemical score was generated. HOXA13 was expressed in the cytoplasm of epithelial cells in normal, hyperplastic and neoplastic prostates. The percentage of immunolabelled cells in all prostatic carcinomas (PCs) was greatly increased, with a score of 85.3 (±5.25) compared with normal (2±0.71) and hyperplastic prostates (6.08±2.21). The increase in HOXA13 expression in canine PCs suggests the involvement of this transcription factor in carcinogenesis and promotion of tumour growth. © 2013 Elsevier Ltd.

Breda M.,Accelera Srl | Baratte S.,Accelera Srl
Analytical and Bioanalytical Chemistry | Year: 2010

5-Fluorouracil (5-FU) is a cytostatic agent that has been widely used in the treatment of various solid tumours for more than 20 years, and is still considered to be among the most active antineoplastic agents in advanced colorectal cancer and malignancies of the head and neck. A large number of non-chromatographic and chromatographic methods for the quantitation of 5-FU, related prodrugs and their metabolites in biological matrices have been developed in the last 30 years to support preclinical and clinical studies. However, 5-FU monitoring has not been widely used, at least not in the USA, and certainly not outside the clinical research setting, given the absence of simple, fast and inexpensive testing methods for 5-FU monitoring. Recent developments with testing based on liquid chromatography-tandem mass spectrometry and a nanoparticle antibody-based immunoassay may facilitate routine monitoring of 5-FU in daily clinical practice. In this review the advantages and disadvantages of the bioanalytical methods developed and used for 5-FU, its metabolites and related prodrugs are discussed. © Springer-Verlag 2010.

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