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Sammichele di Bari, Italy

Guarini A.,Haematology Unit | Minoia C.,Haematology Unit | Giannoccaro M.,Haematology Unit | Rana A.,Haematology Unit | And 6 more authors.
Current Medicinal Chemistry | Year: 2012

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy. © 2012 Bentham Science Publishers.

Numico G.,Science Oncologia | Silvestris N.,Medical and Experimental Oncology Unit | Russi E.G.,Science Radioterapia Oncologica
Frontiers in Bioscience - Scholar | Year: 2011

Initial research showed that EGFR targeting through known single agents, both monoclonal antibodies and small-molecule tyrosine-kinase inhibitors, applied to patients with refractory head and neck cancer, resulted in low response rates and short median survival times. However, the combination of Cetuximab with radiotherapy in patients with locally advanced disease and with a combination of platinum and fluorouracil in the setting of relapsed and/or metastatic disease resulted in a sharp improvement compared to standard therapy. Cetuximab entered clinical practice in both indications. Other anti- EGFR drugs, although showing activity, have not demonstrated an improvement of the results of standard therapy. Unfortunately, no molecular parameter emerged as a useful tool in predicting activity, thus impairing clinical applications. Only skin rash was repeatedly shown to be related with drug activity. Although generally well tolerated, class and drug specific toxicities can be troublesome and require knowledge and expertise for an optimal management. Further research is needed in order to find the best ways of integrating the anti-EGFR strategy with current standards of care.

Bellizzi A.,National Cancer Center Giovanni Paolo | Sebastian S.,National Cancer Center Giovanni Paolo | Ceglia P.,National Cancer Center Giovanni Paolo | Centonze M.,National Cancer Center Giovanni Paolo | And 13 more authors.
Journal of Cellular Physiology | Year: 2013

Although relatively good therapeutic results are achieved in non-advanced cancer, the prognosis of the advanced colon cancer still remains poor, dependent on local or distant recurrence of the disease. One of the factors responsible for recurrence is supposed to be cancer stem cells (CSCs) or tumor-initiating cells, which are a population of cancer cells with ability to perpetuate themselves through self-renewal and to generate differentiated cells, thought to be responsible for tumor recurrence. This study globally approach the possible role of tissue-derived stem cells in the initiation of colon cancer and its metastatic process in the liver. Fresh surgical specimens from colon cancer, non-tumor tissue and liver metastasis were obtained directly from the operating room, examined, and immediately processed. CSCs were selected under serum-free conditions and characterized by CD44 and CD133 expression levels. CD133+/CD44+ cell populations were then investigated in paraffin-embedded tissues and circulating tumor cells isolated from peripheral blood of the same group of colon cancer patients. Our data demonstrate that metastatic properties of cell populations from blood and liver metastasis, differently from primitive tumors, seem to be strictly related to the phenotype CD133 positive and CD44 positive. © 2012 Wiley Periodicals, Inc.

Porcelli L.,National Cancer Research Center Giovanni Paolo | Quatrale A.E.,National Cancer Research Center Giovanni Paolo | Mantuano P.,National Cancer Research Center Giovanni Paolo | Leo M.G.,Health-U | And 6 more authors.
Molecular Oncology | Year: 2013

Cancer cells may use PARP enzymes and Homologous Recombination to repair single and double strand breaks caused by genotoxic insults. In this study, the PARP-1 inhibitor Rucaparib was utilized to increase the sensitivity to chemoradiotherapy treatment in BRCA-2-deficient and -proficient pancreatic cancer cells. We used the pancreatic cancer cell lines, Capan-1 with mutated BRCA-2 and Panc-1, AsPC-1 and MiaPaCa-2 with BRCA-1/2 wild type. Cells were treated with Rucaparib and/or radiotherapy (4-10 Gy) plus Gemcitabine then the capability to proliferate was evaluated by colony formation, cell counting and MTT assays. Flow cytometry, immunocytochemistry and western blotting were utilized to assess cell response to Rucaparib plus irradiation. The antitumour effectiveness of combining the PARP-1 inhibitor before, together and after radiotherapy evidenced the first as the optimal schedule in blocking cell growth. Pre-exposure to Rucaparib increased the cytotoxicity of Gemcitabine plus radiotherapy by heavily inducing the accumulation of cells in G2/M phase, impairing mitosis and finally inducing apoptosis and authophagy. The upregulation of p-Akt and downregulation of p53 were evidenced in MiaPaCa-2 which displayed replication stress features. For the first time, the rationale of using a PARP inhibitor as chemoradiosensitizer in pancreatic cancer models has been hypothesized and demonstrated. © 2012 Federation of European Biochemical Societies.

Silvestris N.,Medical and Experimental Oncology Unit | Marech I.,Interventional Radiology Unit | Brunetti A.E.,Medical and Experimental Oncology Unit | Azzariti A.,National Cancer Research Center Giovanni Paolo | And 6 more authors.
Cancer Biomarkers | Year: 2014

Most cancers are traditionally treated with either chemotherapeutic agents, radiotherapy, or both. Identification of specific molecular characteristics of tumors and the advent of molecular-targeted drugs not only enhance the efficacy but also decrease the toxicity of treatment. These new therapies may target pathways critical to tumor development or specific driver mutations in cancer cells. This understanding of the molecular pathways of cancer cells has led to the ability to predict cancer development, behaviour and prognosis, as well as response or resistance to current therapeutic agents. As a result, pathologic analyses play a vital role in the detection of cancer biomarkers, which are important not only in the diagnosis of cancers but also in the selection of appropriate therapeutic agents and in the development of new targeted therapies. © 2014 - IOS Press and the authors.

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