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.
Germani M.,Accelera S.r.l. |
Del Bene F.,Accelera S.r.l. |
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.
Aguzzi M.S.,Instituto Dermopatico dellImmacolata |
Faraone D.,Instituto Dermopatico dellImmacolata |
D'Arcangelo D.,Instituto Dermopatico dellImmacolata |
De Marchis F.,Instituto Dermopatico dellImmacolata |
And 5 more authors.
Molecular Therapy | Year: 2011
Previous data report that fibroblast growth factor-2 (FGF-2)-derived peptide FREG potently inhibits FGF-2-dependent angiogenesis in vitro and in vivo. Here, we show that FREG inhibits up to 70% in vitro growth and invasion/migration of smooth muscle and melanoma cells. Such inhibition is mediated by platelet-derived growth factor-receptor-α (PDGF-Rα); in fact, proliferation and migration were restored upon PDGF-Rα neutralization. Further experiments demonstrated that FREG interacts with PDGF-Rα both in vitro and in vivo and stimulates its phosphorylation. We have previously shown that overexpressing PDGF-Rα strongly inhibits melanoma growth in vivo; we, therefore, hypothesized that PDGF-Rα agonists may represent a novel tool to inhibit melanoma growth in vivo. To support this hypothesis, FREG was inoculated intravenously (i.v.) in a mouse melanoma model and markedly inhibited pulmonary metastases formation. Immunohistochemical analyses showed less proliferation, less angiogenesis, and more apoptosis in metastasized lungs upon FREG treatment, as compared to untreated controls. Finally, in preliminary acute toxicity studies, FREG showed no toxicity signs in healthy animals, and neither microscopic nor macroscopic toxicity at the liver, kidney, and lungs level. Altogether, these data indicate that FREG systemic treatment strongly inhibits melanoma metastases development and indicate for the first time that agonists of PDGF-Rα may control melanoma both in vitro and in vivo. © The American Society of Gene & Cell Therapy.
Consalvi S.,IRCCS Fondazione Santa Lucia |
Mozzetta C.,IRCCS Fondazione Santa Lucia |
Bettica P.,Italfarmaco SpA |
Germani M.,Accelera SpA |
And 9 more authors.
Molecular Medicine | Year: 2013
Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice-the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.
PubMed | Nerviano Medical science Srl and Accelera Srl
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.
Longo M.,Accelera S.r.l. |
Torre P.D.,Accelera S.r.l. |
Allievi C.,CTI Expert Consultant |
Morisetti A.,CTI Expert Consultant |
And 2 more authors.
Reproductive Toxicology | Year: 2014
The tolerability of pixantrone dimaleate (Pixuvri®), an aza-anthracenedione for non-Hodgkin lymphoma, was assessed in juvenile mice after intraperitoneal injection. Twenty animals/sex/dose received pixantrone 15 or 27. mg/kg/day on Post-Natal-Days (PND) 10, 13, 17, 20, 35, 39 and 42 in comparison with doxorubicin, 3. mg/kg/day. Animals were sacrificed on PND 42, 73 and 96.All pixantrone animals survived, while doxorubicin induced 52.5% mortality and the surviving animals were sacrificed early due to severe toxicity. Recoverable bone marrow toxicity (pixantrone), and toxicity to thymus and reproductive organs (pixantrone, doxorubicin) were observed without nephro- or hepatotoxicity. Pixantrone was measurable in plasma up to 2h (occasionally 6h) post-dose. At PND 42, mean Cmax and AUC values increased proportionally with dose, without gender difference or accumulation.Pixantrone showed minimal cardiotoxicity in males and negligible in females at PND 96. Doxorubicin induced significant heart weight reduction at PND 42, however early sacrifice impeded further cardiac assessments. © 2014 Elsevier Inc.
Palmieri C.,University of Queensland |
Riccardi E.,Accelera S.r.l.
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 S.r.l. |
Baratte S.,Accelera S.r.l.
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.
Germani M.,Accelera S.r.l. |
Del Bene F.,Accelera S.r.l. |
Rocchetti M.,Accelera S.r.l. |
Van Der Graaf P.H.,Pfizer
Computer Methods and Programs in Biomedicine | Year: 2013
Effective communication of PK/PD principles and results in a biomedical research environment remains a significant challenge which can result in lack of buy-in and engagement from scientists outside the modeling and simulation communities. In our view, one of the barriers in this area is a lack of user-friendly tools which allow " non experts" to use PK/PD models without the need to develop technical skills and expertise in advanced mathematical principles and specialist software. The costs of commercial software may also prevent large-scale distribution. One attempt to address this issue internally in our research organizations has resulted in the development of the A4S (" Accelera for Sandwich" ) software, which is a simple-to-use, menu-drive Matlab-based PK/PD simulator targeted at biomedical researchers with little PK/PD experience. © 2012 Elsevier Ireland Ltd.
Magni P.,University of Pavia |
Terranova N.,University of Pavia |
Del Bene F.,Accelera Srl |
Germani M.,Accelera Srl |
De Nicolao G.,University of Pavia
IEEE Transactions on Biomedical Engineering | Year: 2012
One important issue in the preclinical development of an anticancer drug is the assessment of the compound under investigation when administered in combination with other drugs. Several experiments are routinely conducted in xenograft mice to evaluate if drugs interact or not. Experimental data are generally qualitatively analyzed on empirical basis. The ability of deriving from single drug experiments a reference response to the joint administrations, assuming no interaction, and comparing it to real responses would be key to recognize synergic and antagonist compounds. Therefore, in this paper, the minimal model of tumor growth inhibition (TGI), previously developed for a single drug, is reformulated to account for the effects of noninteracting drugs and simulate, under this hypothesis, combination regimens. The model is derived from a minimal set of basic assumptions that include and extend those formulated at cellular level for the single drug administration. The tumor growth dynamics is well approximated by the deterministic evolution of its expected value that is obtained through the solution of an ordinary and several partial differential equations. Under suitable assumptions on the cell death process, the model reduces to a lumped parameter model that represents the extension of the very popular Simeoni TGI model to the combined administration of noninteracting drugs. © 2012 IEEE.