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Gasparini P.,Molecular Cytogenetics Unit | Bertolini G.,Molecular Cytogenetics Unit | Binda M.,Translational Research Unit | Magnifico A.,Molecular Targeting Unit | And 9 more authors.
Cancer Letters | Year: 2010

There is indication that tumor growth is sustained by subpopulation of cells with stem-like features but little is known on their genomic characterization and their genetic stability. We report a detailed molecular cytogenetic characterization using Spectral Karyotyping and fluorescent in situ hybridization of parental serum-cultured adherent cells and their sphere-growing stem-like counterpart before and after differentiation from six cell lines established from solid tumors. Our findings indicate increased cytogenetic complexity in sphere-growing stem-like and their differentiated adherent cells compared to parental adherent component suggesting the existence within cell lines of heterogeneous and genetically unstable subpopulations of cells endowed with stem-like features. © 2010 Elsevier Ireland Ltd. Source

De Cesare M.,Preclinical Chemotherapy and Pharmacology Unit | Sfondrini L.,Molecular Biology Unit | Campiglio M.,University of Milan | Sommariva M.,Molecular Biology Unit | And 9 more authors.
Journal of Immunotherapy | Year: 2010

Tumor cell growth, even in advanced stages of ovarian cancer, is nearly always restricted to the peritoneal cavity; therefore, repeated intraperitoneal injections of oligodeoxynucleotides containing dinucleotides with unmethylated CpG motifs (CpG-ODN) recruiting and activating innate effector cells throughout the abdominal cavity to the tumor site might control tumor cell growth and ascites formation. After a single CpG-ODN treatment, in IGROV-1 ovarian tumor ascites-bearing athymic mice, the number of tumor cells declined rapidly and markedly, and ascites volumes declined shortly after treatment (5h), increasing thereafter at a slower rate than in controls. When administered every 7 days for 4 weeks, CpG-ODN had only a marginal effect on survival time, whereas administration 5 days/wk for 3 or 4 weeks led to a significantly increased survival time as compared with controls (P<0.005) and completely controlled ascites growth without apparent toxicity, although a disorganization of lymphoid organs was observed. Bio-plex assay of cytokine levels in peritoneal fluid of ascites-bearing mice after CpG-ODN treatment revealed an increase in interleukin (IL)-6, IL-10, IL-12, and interferon-γ at 24 hours, which returned to control mice levels at 48 to 96 hours, whereas the high levels of angiogenic factors remained unchanged. Depletion of natural killer or monocytes/macrophages only slightly influenced the CpG-ODN-induced reduction of ascites tumor cells, indicating that the antitumor activity might not be related to a specific cell/cytokine but rather to the repertoire of cells and cytokines accumulated in the peritoneal cavity. Thus, our data suggest a relevant role for repeated activation of cells and cytokines of innate immunity in the therapy of ovarian cancer patients with malignant ascites. © 2009 by Lippincott Williams & Wilkins. Source

Gatti L.,Preclinical Chemotherapy and Pharmacology Unit | Perego P.,Preclinical Chemotherapy and Pharmacology Unit | Leone R.,University of Verona | Apostoli P.,University of Brescia | And 13 more authors.
Molecular Pharmaceutics | Year: 2010

Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (biscapronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development. © 2010 American Chemical Society. Source

Zuco V.,Preclinical Chemotherapy and Pharmacology Unit | Benedetti V.,Preclinical Chemotherapy and Pharmacology Unit | De Cesare M.,Preclinical Chemotherapy and Pharmacology Unit | Zunino F.,Preclinical Chemotherapy and Pharmacology Unit
International Journal of Cancer | Year: 2010

The synthetic atypical retinoids containing an adamantyl group exhibit antiproliferative or proapoptotic activities. Apoptosis induction is a dose-dependent effect independent of retinoid receptors. We have reported that induction of apoptosis by the atypical retinoid, ST1926, is associated with early manifestations of genotoxic stress. Indeed, in this study performed in ovarian carcinoma cells, we show that exposure to ST1926 resulted in an increase of early markers of DNA damage, including ATM and H2AX phosphorylation. In addition, we found that a novel histone deacetylase (HDAC) inhibitor (RC307) was able to enhance sensitivity of ovarian carcinoma cells to ST1926. Under conditions where single-agent treatment caused only antiproliferative effects, the combination of the atypical retinoid and HDAC inhibitor resulted in marked apoptotic cell death with a more rapid onset in wild-type p53 ovarian carcinoma cells. The sensitization to ST1926-induced apoptosis was associated with an enhanced DNA damage response, because a prolonged expression of DNA damage markers (e.g., H2AX, p53 and RPA-2 phosphorylation) and a marked activation of DNA damage checkpoint kinases (in particular, phosphorylation of Chk1) were observed indicating an accumulation of DNA damage by the ST1926/HDAC inhibitor combination. The study provides additional support to the role of DNA damage as a primary event leading to the activation of apoptosis in ovarian carcinoma cells by adamantyl retinoids and documents the potential therapeutic efficacy of the combination of ST1926 and HDAC inhibitors of the novel series. © 2009 UICC. Source

Pizzamiglio S.,Medical Statistics and Biometry Unit | Cossa G.,Preclinical Chemotherapy and Pharmacology Unit | Gatti L.,Preclinical Chemotherapy and Pharmacology Unit | Beretta G.L.,Preclinical Chemotherapy and Pharmacology Unit | And 4 more authors.
Oncology Reports | Year: 2010

The rapid evolution of techniques for measuring gene expression makes available substantial data which require careful analysis. In particular, relative quantification based on microfluidic cards allows performing of rapid large scale analyses. In the present study, we employed ovarian carcinoma cell lines resistant to cisplatin (IGROV-1/Pt1) or to a camptothecin (IGROV-1CPT/L), both characterized by a complex pattern of resistance to multiple agents, to examine the expression of genes of the superfamily of ATP binding-cassette (ABC) transporters by TaqMan microfluidic cards with the aim of developing an analytical tool to process data in this particular framework. The transcript quantification was based on the comparative threshold cycle method, which compares the expression of a target gene normalized to the expression of one or more reference genes (relative quantification). To process expression of ABC transporters, we applied a statistical procedure based on multivariate approaches and re-sampling techniques. The transporters that were significantly modulated included members of the ABCA, ABCB, ABCC and ABCG subgroups. A consistent up-regulation of ABCC2 as compared with the parental IGROV-1 cell line was observed in the IGROV-1/Pt1 cells, whereas down-regulation of ABCC6 and ABCG1 was found in IGROV-1/ CPT-L cells. The use of rigorous analytic tools for gene expression data in preclinical models may lead to the identification of signatures to test in ovarian carcinoma clinical samples. Moreover, the developed procedure may be useful in the analysis of relative quantification data obtained with microfluidic cards in different experimental settings. Source

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