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Genova, Italy

Frosina G.,Mutagenesis Unit
Critical Reviews in Oncology/Hematology | Year: 2015

Glioblastoma (GB - WHO grade IV) is the most frequent and lethal primary brain tumour with median overall survival of 7-15 months after diagnosis. As in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field have not been translated to patients' benefit, potentially due to inappropriate treatment schedules and/or trial designs in the clinical setting. The recent failure of promising anti-VEGF bevacizumab to improve GB patients' overall survival recapitulates this sense of frustration. The following measures are proposed:. 1.to change Phase II design. Bevacizumab and other drugs may have failed in Phase III just because of an inappropriate clinical treatment schedule adopted. Multiple-step Phase II clinical trials allowing more thorough definition of treatment protocols to be extensively studied in Phase III should be designed.2.to monitor standards of care by documenting survival rates of GB patients in European Cancer Units, in order to homogenize GB treatment quality to the highest possible level all over EU28.3.to introduce the therapeutic impact factor (TIF) and therapeutic (t) index bibliometric parameters, in order to orientate pre-clinical research toward more therapy-focussed activities. © 2015 Elsevier Ireland Ltd. Source

Izzotti A.,Mutagenesis Unit | Izzotti A.,University of Genoa | La Maestra S.,University of Genoa | Micale R.T.,University of Genoa | And 2 more authors.
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2015

Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized. © 2014 Elsevier B.V. Source

Frosina G.,Mutagenesis Unit
Current Medicinal Chemistry | Year: 2015

Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current status of clinical research on GB, a literature search was conducted in PubMed using the terms: "glioma AND trial" over a 500 day period elapsing from Jan 1, 2013 to May 15, 2014 and results of Phase I, II and III trials were reviewed. Results in the pediatric setting were included as well. It was concluded that, as in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field are not presently translated to improved patients' survival. In order to explore novel therapeutic avenues for this deadly tumour, two innovative medicinal chemistry approaches are proposed and discussed: a) Specific glioma initiating cell-radiosensitization by ATM inhibitors [1] and b) Specific glioma initiating cell-chemotherapeutic targeting by MYC inhibitors [2]. © 2015 Bentham Science Publishers. Source

Viadiu H.,National Autonomous University of Mexico | Fronza G.,Mutagenesis Unit | Inga A.,University of Trento
Sub-Cellular Biochemistry | Year: 2014

The design of a broad-spectrum cancer drug would provide enormous clinical benefits to treat cancer patients. Most of cancerous cells have a mutation in the p53 gene that results in an inactive mutant p53 protein. For this reason, p53 is a prime target for the development of a broad-spectrum cancer drug. To provide the atomic information to rationally design a drug to recover p53 activity is the main goal of the structural studies on mutant p53. We review three mechanisms that influence p53 activity and provide information about how reactivation of mutant p53 can be achieved: stabilization of the active conformation of the DNA-binding domain of the protein, suppression of missense mutations in the DNA-binding domain by a second- site mutation, and increased transactivation. © Springer Science+Business Media Dordrecht 2014. Source

Frosina G.,Mutagenesis Unit
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2016

High grade gliomas (HGGs) are fatal brain tumors due to their infiltration capacity and the presence of resistant cell populations. Further, the brain is naturally protected from many exogenous molecules by the brain blood barrier (BBB), which limits or cancels passage of cytotoxic drugs to the tumor sites. In order to cope with the latter problem, nanoparticle (NP)-based carriers are intensively investigated, due to multiple possibilities to drive them across the BBB to the tumor sites and drop cytotoxic molecules there. The current status of research on NP for drug delivery to HGGs has been analyzed. The results indicate gold, lipids and proteins as three main materials featuring NP formulations for HGG treatment. Albeit specific drug targeting to HGG cells may have not been so far significantly improved, NP may help drugs crossing the BBB and enter the brain thus potentially fixing at least one part of the problem. © 2016 Elsevier Inc. Source

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