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Graziano F.,Azienda Ospedaliera Ospedali Riuniti Marche Nord
Pharmacogenomics Journal | Year: 2016

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.The Pharmacogenomics Journal advance online publication, 1 March 2016; doi:10.1038/tpj.2016.13. © 2016 Macmillan Publishers Limited

Fiorentini G.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | Banfi R.,Azienda Ospedaliera Careggi | Dentico P.,Units of Oncology and Pharmacology | Moriconi S.,Units of Oncology and Pharmacology | And 4 more authors.
In Vivo | Year: 2013

Background: Diphtheria toxin (DT) has shown anticancer activity in both experimental models and humans but its adverse effects stopped further developments. Crossreacting Material 197 (CRM197) is the product of a single missense mutation (Gly52 to Glu) within fragment A of DT. It has been shown to induce weak toxicity in some cell strains, but it shares immunological properties with native DT. CRM197 commonly acts as an immunological adjuvant, or as an inhibitor of heparin-binding epidermal growth factor. Recently, CRM197 was shown to have promising antitumor activity. To better-define this property, we planned a phase III study. Patients and Methods: Twenty-nine patients bearing advanced melanoma (18 cases), and other solid tumors (two ovarian cancer, two sarcoma, two gastrointestinal cancers, one urinary bladder carcinoma, one glioblastoma, one neuroblastoma, one ocular melanoma and one primitive neuroectodermal embriogenic tumor (PNET) were evaluated and 19 of them, sub-divided in cohorts, received the following levels of CRM197: Level 1, 0.3 mg; level 2, 1.0 mg; level 3, 2.5 mg; level 4, 3.5 mg; level 5, 5.0 mg; level 6, 7.5 mg. The drug was given once every two days for 4 times and then, after a 2-week rest period, once every 2 days for 4 times. CRM197 was administered subcutaneously in the abdominal wall. Results: grade 1-2 common toxicities included fever, chills, fatigue, dizziness, nausea, vomiting and headache, neutrophilia and skin painful reactions appeared regularly at levels 3 and 4 (2.5 mg and 3.5 mg). Vomiting and abdominal pain, skin reaction tachycardia and hypotension appeared in two patients at level 5. At 7.5 mg, we observed a severe grade 3 reaction with hypotension, dyspnea and grade 4 myalgia. This was considered the dose-limiting toxicity. Eleven patients (seven with melanoma and four with other tumors) were treated to evaluate anticancer effects at the maximum tolerated dose (5 mg). Only one patient reported a minor response, lasting eight weeks. Ten patients reported progressive disease. Conclusion: CRM197, injected subcutaneously at 5 mg, elicited a generic inflammatory response causing toxicity, and did not exert a significant degree of antitumor activity in patients with advanced melanoma and solid tumour.

Ruzzo A.,Urbino University | Graziano F.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | Galli F.,Laboratorio Of Ricerca Clinica | Giacomini E.,Urbino University | And 23 more authors.
Scientific Reports | Year: 2014

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II-III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3-4 CTCAE toxicity events (grade 2-4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Fiorentini G.,Oncology Unit | Aliberti C.,Interventional Radiology Unit | Mulazzani L.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | Coschiera P.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | And 4 more authors.
Anticancer Research | Year: 2014

Currently image-guided trans-arterial chemoembolization (TACE) has a significant role in the therapy of patients with hepatocellular carcinoma and liver metastases. This endovascular hepatic-directed therapy offers the dual benefit of true local neoplastic control and reduction of side-effects. As a result, it has been included in the guidelines for primary liver cancer and is often considered as salvage therapy for patients liver metastases from neuroendocrine and chemorefractory colorectal tumors. The development of new embolizing agents, such as DC beads loaded with doxorubicin and irinotecan, permits better standardization and definition of protocols, making the procedures less linked to criteria of different hospitals and personal experiences of interventional radiologists. The understanding that hypoxia induces vessel regrowth will open a new avenue for clinical research and a rebirth for TACE. Chemoembolization followed by target therapy (bevacizumab, aflibercept and regorafenib) could increase quality, duration of responses and better quality of life. © 2014, International Institute of Anticancer Research. All rights reserved.

Ruzzo A.,Urbino University | Catalano V.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | Canestrari E.,University of Illinois at Chicago | Giacomini E.,Urbino University | And 6 more authors.
BMC Cancer | Year: 2014

Background: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. Methods: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). Results: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. Conclusions: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients. © 2014 Ruzzo et al.; licensee BioMed Central Ltd.

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