[show abstract][hide abstract] ABSTRACT: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer.
Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety.
There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B.
This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.
Annals of Oncology 09/2011; 23(5):1121-9. · 7.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Triple-negative breast cancers (TNBCs) lack expression of oestrogen, progesterone, and Human Epidermal Growth Factor 2 receptors. The NEMESI study described current Italian treatment practices in patients with operable, early-stage breast cancer (EBC).
Retrospective, observational study involving 63 Italian oncology centres. Eligible patients were aged ≥ 18 years with EBC (stage I-II) who had undergone surgery, received ≥ 1 cycle of adjuvant chemotherapy and/or adjuvant hormonal therapy and attended an oncology centre between 1 January 2008 and 30 June 2008. This subanalysis focused on patients with TNBC. Variables evaluated included: demographic data/clinical characteristics; tumour characteristics; adjuvant therapy; compliance to chemotherapy. Continuous variables were summarised using descriptive statistics.
Of 1894 patients in the NEMESI study, 185 patients (9.8%) had TNBC. At diagnosis, 98 patients were aged 50-70 years and 114 were post-menopausal. Tumours were subcategorised as pT1mic/pT1a/pT1b/pT1c in 108 patients and pT2/pT3/pT4b in 77 patients. Mean tumour size was 2.1cm, tumours were highly undifferentiated in 144 patients and 128 patients were pNO. 179 patients received adjuvant chemotherapy; anthracyclines with or without taxanes were commonly used. 145 patients received radiotherapy.
Adherence of Italian clinical practice to International Guidelines in the management of early-stage TNBC is satisfactory.
European journal of cancer (Oxford, England: 1990) 07/2011; 48(5):642-7. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: The role of EGFR in cancer development and progression has been recognized for long time in a variety of human malignancies including lung, head and neck, colon, breast, ovary and glioma. Recently its role as a target of antineoplastic agents has also been identified and a variety of EGFR-targeted drugs is already being used in a clinical setting and others are at present under investigation. Many data involving EGFR protein expression are now available for the choice of anti-EGFR monoclonal antibodies in colorectal cancer and with regard to EGFR gene mutations for the choice of tyrosine kinase inhibitors in lung cancer. Other EGFR-related molecular factors, including the EGFR gene copy number, are currently under investigation. This review summarizes both preclinical and clinical available data regarding EGFR genomic alterations as prognostic and predictive factors.
Frontiers in bioscience (Elite edition) 01/2011; 3:879-87.
[show abstract][hide abstract] ABSTRACT: The adenocarcinoma of the lung has recently shown peculiar molecular characteristics, which relate with both carcinogenesis and response to targeted drugs. Several molecular alterations have been defined as "driver mutations". These are responsible for both the initiation and maintenance of the malignancy. The epidermal growth factor receptor (EGFR) pathway is the main regulator of cell function and cancer development. It has a widely defined role in the occurrence of driver mutations. Up till now EGFR gene mutations, KRAS gene mutations and EML4-ALK fusion genes are the most widely recognized alterations involved in both the biology and the clinical management of lung adenocarcinoma. In this review we report the molecular bases that have led to the clinical application of the detection for such genetic impairments. Subsequently we discuss the clinical studies regarding the prognostic role and the predictive value for response to anti-EGFR tyrosine kinase inhibitors (TKI) of the same mutations. We also provide a potential algorithm as a guide in the choice of the best treatment for patients with adenocarcinoma.
[show abstract][hide abstract] ABSTRACT: An important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.
[show abstract][hide abstract] ABSTRACT: To date, little is known concerning the promyelocytic leukemia gene (PML) status in tumors of different origin, and its expression has never been evaluated in soft tissue sarcoma. The aim of the present study is focused on the identification of differences in terms of PML protein expression between different types of soft tissue sarcoma and the corresponding normal surrounding tissue. PML protein expression has been assessed by immunohistochemistry in six different histologic types of soft tissue sarcoma (synovial sarcoma, myofibroblastic sarcoma, angiosarcoma, liposarcoma, pleomorphic sarcoma, and leiomyosarcoma) and in the corresponding normal surrounding tissue. PML resulted significantly down-regulated in synovial sarcoma and in myofibroblastic sarcoma specimens. Also in angiosarcoma samples a significative difference in PML expression in comparison with normal specimens has been detected. Interestingly PML protein detection showed a different pattern of expression in the three liposarcoma histology types compared with corresponding nontumoral tissues. In particular PML protein resulted significantly down-regulated in myxoid liposarcoma and in dedifferentiated liposarcoma. On the contrary no statistically significant difference was observed in pleomorphic liposarcoma compared to normal tissue specimens. Further investigations are needed to confirm these data and to assess the possible value of PML expression as a prognostic factor in these extremely aggressive diseases.
Journal of Cellular Physiology 09/2010; 224(3):644-8. · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: A weekly administration of alternating irinotecan or oxaliplatin associated to 5-Fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).
[show abstract][hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of different genes, including genes involved in cancer progression. A functional link between hypoxia, a key feature of the tumor microenvironment, and miRNA expression has been documented. We investigated whether and how miR-20b can regulate the expression of vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells under normoxic and hypoxia-mimicking conditions (CoCl(2) exposure). Using immunoblotting, ELISA, and quantitative real-time PCR, we demonstrated that miR-20b decreased VEGF protein levels at 4 and 24 h following CoCl(2) treatment, and VEGF mRNA at 4 h of treatment. In addition, miR-20b reduced VEGF protein expression in untreated cells. Next, we investigated the molecular mechanism by which pre-miR-20b can affect VEGF transcription, focusing on hypoxia inducible factor 1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), transcriptional inducers of VEGF and putative targets of miR-20b. Downregulation of VEGF mRNA by miR-20b under a 4 h of CoCl(2) treatment was associated with reduced levels of nuclear HIF-1 alpha subunit and STAT3. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-1 alpha, but not STAT3, was recruited to the VEGF promoter following the 4 h of CoCl(2) treatment. This effect was inhibited by transfection of cells with pre-miR-20b. In addition, using siRNA knockdown, we demonstrated that the presence of STAT3 is necessary for CoCl(2)-mediated HIF-1 alpha nuclear accumulation and recruitment on VEGF promoter. In summary, this report demonstrates, for the first time, that the VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner.
Journal of Cellular Physiology 03/2010; 224(1):242-9. · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: The endothelin (ET) axis, which includes the biological functions of ETs and their receptors, has played a physiological role in normal tissue, acting as a modulator of vasomotor tone, tissue differentiation and development, cell proliferation and hormone production. Interestingly, it also functions in the growth and progression of various tumors. Several researchers have identified the blockade of the ET-1 receptor as a promising therapeutic approach.
The clinical investigation of an orally bioavailable ET antagonist, atrasentan, in prostate cancer, is encouraging. In this neoplasia, it has shown antitumor activity, bone metastasis control and amelioration of cancer-related pain but improvement in time to progression and overall survival has still not been demonstrated. The clinical trials of other ET antagonists are reported. Literature research was performed by Pubmed and Pharmaprojects.
A comprehensive view about the use of atrasentan in the treatment of castration-resistant prostate cancer (CRPC) is provided together with the scientific rationale based on the function of ET and its receptor in various cancer development mechanisms.
Atrasentan seems to be active in CRPC, although strong scientific evidence is still to be found. Interesting clinical findings regard zibotentan.
[show abstract][hide abstract] ABSTRACT: Bortezomib is a proteasome inhibitor. It targets the ubiquitin-proteasome pathway with subsequent inhibition of the degradation of proteins involved in cell cycle regulation and cancer cell survival. The best known molecular mechanism concerns the inhibition of IκB breakdown and the related stabilization of NFκB, thus preventing its translocation to the nucleus for the activation of downstream pathways. Bortezomib is the only drug in this class which has been approved for clinical use. It has shown an efficient antitumor effect in a phase III clinical trial (APEX) involving relapsed multiple myeloma patients. Response rate, time to progression and overall survival have been improved in patients treated with bortezomib and dexamethasone compared to dexamethasone alone. These results have induced several researchers to suggest preclinical and clinical studies for the application of bortezomib in solid tumors. Preclinical data have proved useful in the identification of several of the biological processes implicated, including cell cycle arrest at the G2/M phase, upregulation of p21, apoptosis regulation, microvessel density reduction, overcoming chemotherapy resistance. The clinical results obtained so far with the use of bortezomib in patients with solid malignancies are still not sufficient for the introduction of the drug into clinical practice. Furthermore, the results obtained with the use of bortezomib combined with cytotoxic drugs have not proved any more satisfactory than those obtained with bortezomib used as a single agent. Other preclinical studies are required in order to reach a clearer understanding of the relevance of bortezomib in the therapy of solid tumors.
Current Cancer Drug Targets 01/2010; 10(1):55-67. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Imatinib mesylate (Gleevec) is a drug unique for the treatment of certain forms of cancer. It works by targeting, and turning off, specific tyrosine kinase proteins that cause the uncontrolled cell growth and the inhibition of apoptosis in cancer cells. Imatinib was designed on the basis of the structure of the ATP binding site of the Abl protein kinase with the aim to stabilizes the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in chronic myelogenous leukemia (CML). However, imatinib can also target other tyrosine kinase proteins different from Bcr-Abl such as Kit, that is the suspected cause of gastrointestinal stromal tumor (GIST). Despite successful clinical results observed in the last years, the long-term effects of imatinib and its ability to completely eradicate CML are still unknown. Moreover, similar to many other anti-cancer drugs, clinical resistance to imatinib has emerged. In this review we will discuss the in vitro and in vivo results obtained with the novel tyrosine kinase inhibitors developed to overcome imatinib resistance in Bcr-Abl expressing hematologiocal disorders.
Anti-cancer agents in medicinal chemistry 10/2009; 9(8):853-63.
[show abstract][hide abstract] ABSTRACT: : Although platinum-based combinations are considered the best option of care for patients with advanced nonsmall cell lung cancer (NSCLC), single-agent therapy is the preferred treatment for older patients. Since the late 1990s, various combinations of third-generation agents (gemcitabine [G], vinorelbine, docetaxel, and paclitaxel) have been tested, yielding contradictory results. The authors of this report performed a literature-based meta-analysis to assess the efficacy and tolerability of G-based doublets compared with single-agent chemotherapy for elderly patients with NSCLC.
: Data from all published, randomized, phase 3 trials that compared a G-based doublet with a third-generation single agent in elderly patients were collected from electronic databases (Medline and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. Pooled odds ratios (ORs) were calculated for the 1-year survival rate, the overall response rate (ORR), and grade 3 and 4 toxicities.
: Four eligible trials (1436 patients) were selected from 442 studies that initially were identified. A significant difference in ORR favoring G-based doublets over single agents was observed (OR, 0.65; 95% confidence interval [95% CI], 0.51-0.82 [P < .001]), whereas the trend toward an improved 1-year survival rate was not significant (OR, 0.78; 95% CI, 0.57-1.06 [P = .169]). Grade 3 and 4 toxicities did not differ significantly except for thrombocytopenia (OR, 1.76; 95% CI, 1.12-2.76 [P = .014]).
: G-based doublets appeared to be effective and feasible compared with single agents in the treatment of elderly patients with advanced NSCLC who were not suitable for full-dose, platinum-based chemotherapy. Further prospective, elderly specific, phase 3 trials will be necessary. Cancer 2009. (c) 2009 American Cancer Society.
Cancer 03/2009; 115(9):1924-31. · 5.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with metastatic colorectal carcinoma. Among patients not carrying activating mutations in the KRAS gene, only a limited number will experience tumor response to these therapeutic agents. The role of BRAF mutations in determining resistance to this treatment is emerging through preclinical and clinical studies. Standardization and validation of laboratory mutation analysis is needed to allow an optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Clinical single-arm and randomized studies were conducted both in first-line and refractory settings to evaluate the correlation of KRAS mutational status and efficacy of cetuximab and panitumumab. The main trials on first-line regiments are CRYSTAL, which is looking at FOLFIRI (folinic acid, fluorouracil, irinotecan) + cetuximab, and OPUS, which is evaluating FOLFOX (folinic acid, fluorouracil, oxaliplatin) + cetuximab. The results of these trials have induced the European Medicines Agency to apply restrictions to its approval of cetuximab and panitumumab for use in metastatic colorectal cancer patients with wild-type KRAS tumors. However, the absence of KRAS mutations is not sufficient to assure clinical response to cetuximab and panitumumab. We need to discover further molecular biomarkers of impairment in this or other signaling pathways to identify responders more specifically. Preclinical rationale is available for combined therapies, which simultaneously target EGFR and the RAS/RAF/MAPK signaling pathways for metastatic colorectal cancer.
[show abstract][hide abstract] ABSTRACT: A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.
Journal of Medicinal Chemistry 11/2008; 51(21):6800-7. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Resistance to imatinib mesylate is an emergent problem in the treatment of Bcr-Abl expressing myelogenous leukemias and additional therapeutic strategies are required. We observed that galangin, a non-toxic, naturally occurring flavonoid was effective as anti-proliferative, and apoptotic agent in Bcr-Abl expressing K562 and KCL22 cells and in imatinib mesylate resistant K562-R and KCL22-R cells. Galangin induced an arrest of cells in G0-G1phase of cell cycle and a decrease in pRb, cdk4, cdk1, cycline B levels; moreover, it was able to induce a monocytic differentiation of leukemic Bcr-Abl+ cells. Of note, galangin caused a decrease in Bcl-2 levels and markedly increased the apoptotic activity of imatinib both in sensitive or imatinib-resistant Bcr-Abl+ cell lines. In contrast, flavonoids unable to modify the Bcl-2 intracellular levels, such as fisetin and chrysin, did not increase the apoptotic effect of imatinib. These data suggest that galangin is an interesting candidate for a combination therapy in the treatment of imatinib-resistant leukemias.
Cancer Letters 08/2008; 265(2):289-97. · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this continuation of our research on derivatives containing the stilbene privileged structure or that are derived from it, we report the results of further studies carried out on the previously initiated collection of compounds. We used a parallel synthetic approach to rapidly obtain small sets of compounds and started the annotation of the library in progress by calculating some physicochemical properties to be eventually correlated with biological activities. A pharmacophore for the antiproliferative activity was also built to summarize the features of the library. We evaluated the antiproliferative and pro-apoptotic activities of all compounds as well as the cell-cycle effects of some representative compounds. After in-depth investigations, 3'-phenyl-[1,1';4',1'']terphenyl-4,3'',5''-triol showed the most interesting biological profile, as it interferes with cell-cycle progression at the G(1)-->S transition, acting on retinoblastoma phosphorylation and inducing cell differentiation.
[show abstract][hide abstract] ABSTRACT: In this work, we have investigated about the presence of several natural stilbenes in 12 samples of pistachios harvested from 10 different farms of Sicily (Bronte and Agrigento). At the same time, we have evaluated the relation between the stilbenes synthesis and the possible contamination of mycotoxin produced by Aspergillus flavus and Aspergillus parasiticus. We have found two types of stilbenes in the samples of pistachios examined: trans-resveratrol and trans-resveratrol-3-O-β-glucoside (trans-piceid). Their concentration ranged from 0.07 to 0.18 mg/kg (av. = 0.12 ± 0.03 mg/kg) for trans-resveratrol, from 6.20 to 8.15 mg/kg (av. = 6.97 ± 0.55 mg/kg) for trans-piceid and from 6.38 to 8.27 mg/kg (av. = 7.09 ± 0.54 mg/kg) for total resveratrol.