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Francesco Lo Coco

Publications and source records attributed to Francesco Lo Coco.

At least 19 recordsLinked to original sources
PubMed2006

Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4.

Arsenic trioxide (As2O3) is a highly effective agent in the treatment of acute promyelocytic leukemia (APL), whereas other hematopoietic tumors are less responsive to this agent and mechanisms underlying As2O3,-resistance are poorly understood. To better understand the complex network of GSH-related pathways in As2O3 sensitivity, we investigated the role of GSH and GSH-relevant enzymes in an APL cell line sensitive to As2O3 (NB4) and in a resistant subclone (AsR). Cell proliferation, viability, and apoptosis were investigated in NB4 cells before and after treatment with 1 muM As2O3 and in AsR cells. In these experimental cell models, GSTP1-1, JNK1 and JNK2 proteins were analyzed by immunoblotting, and a kinase assay for JNK1 was performed. GSH levels as well as the activities of the enzymes glutathione peroxidase, glutathione transferase, gamma-Glutamylcysteynilsinthetase and superoxide dismutase were measured. NB4 cells treated with As2O3 showed a high level of oxidative stress and an increase of GSH levels. GSTP1-1 polymerization and JNK1 activation were detectable after 24 h and were followed by an increase of the apoptotic rate starting at 72 h. Neither GSTP1-1 polymerization nor JNK activation was found in AsR cells that showed a very low apoptotic rate. Our results suggest that APL sensitivity to As2O3 might be, at least in part, mediated by the balance between association and dissociation of JNK from GSTP1-1, depending on the redox status of the cell. Further investigation is warranted to find a way to interfere with this balance, whenever it might represent a mechanism of drug resistance.

Antineoplastic Agents↗
PubMed2006

Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia.

The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70(+) (P < .001), in CD38(+) (P < .001) and in sCD23(+) patients (P < .001 and P = .013, respectively). ZAP-70(+)CD38(+) or ZAP-70(+) patients with an unmutated IgV(H) status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70(-)/CD38(-) or ZAP-70(-) patients with mutated IgV(H) genes. Discordant patients showed an intermediate outcome. Note, ZAP-70(+) patients even if CD38(-) or mutated showed a shorter PFS, whereas ZAP-70(-) patients even if CD38(+) or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgV(H) gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70(+) patients.

ADP-ribosyl Cyclase 1↗
PubMed2006

Validation of an interphase fluorescence in situ hybridization approach for the detection of MLL gene rearrangements and of the MLL/AF9 fusion in acute myeloid leukemia.

To validate a 2-step FISH assay for the identification of the t(9;11)(p22;q23), 96 acute myeloid leukemias were studied by cytogenetic analysis, FISH and molecular biology. After a first FISH step using an MLL probe, 24/27 cases with 11q23 break showed MLL rearrangement. Southern blotting confirmed FISH data. In the second step, 24 cases with MLL rearrangement were studied using MLL and AF9 probes: 17/18 cases with t(9;11) showed MLL/AF9 fusion. In 6 patients with 11q23/MLL rearrangements other than t(9;11), FISH confirmed MLL involvement and excluded AF9 involvement. This is a reliable method for the identification of MLL/AF9 fusion in interphase cells, allowing for a reclassification of cases with suboptimal chromosome morphology. The frequency of deletion surrounding MLL and AF9 breakpoint is low.

Gene Rearrangement↗
PubMed2006

Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin.

Acute promyelocytic leukemia (APL) is a form of acute myeloid leukemia characterized by peculiar biologic features and a unique sensitivity to differentiation therapy with all-trans retinoic acid (ATRA). Modern treatment approaches to APL include simultaneous combination of ATRA and anthracycline-based chemotherapy. Gemtuzumab ozogamicin is a calicheamicin-conjugated monoclonal antibody directed against CD33, a cell surface antigen highly expressed on APL cells. Engagement of CD33 by gemtuzumab results in immunoconjugate internalization and hydrolytic release of calicheamicin, which, in turn, causes irreversible DNA damage and cell death. A number of preliminary reports have highlighted the sensitivity of APL to gemtuzumab given alone or in combination with other agents. Several reasons may account for the efficacy of gemtuzumab in APL, including: (1) CD33 is detectable in virtually 100% of APL cases; (2) calicheamicin belongs to the anthracycline family, a group of chemotherapeutic agents known to be highly effective in APL; and (3) the APL blast cells lack the multidrug resistance glycoprotein 170. Due to the availability of other highly effective agents (ATRA, arsenic trioxide), relatively few APL patients have been treated thus far with gemtuzumab, and their follow-up is still short. However, it is conceivable that the use of this agent in APL will increase in the near future in light of its capability to induce molecular remission even in advanced disease. Furthermore, the use of low doses of gemtuzumab in high-risk patients might be relevant in order to reduce treatment toxicity due to conventional anthracyclines. This review summarizes the mechanism of action and toxicity profile of gemtuzumab as well as the published experience with this compound in patients with newly diagnosed and relapsed APL.

Aminoglycosides↗
PubMed2005

The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP-70-negative chronic lymphocytic leukemia.

BACKGROUND: Clinical trials of monoclonal antibodies in combination with chemotherapy have reported previously unattained response rates in patients with B-cell chronic lymphocytic leukemia (B-CLL); however, the analysis of ZAP-70 protein and/or CD38 may explain better the discordant outcomes independent of treatment. METHODS: The authors conducted a Phase II study, in which rituximab was added to fludarabine for patients with symptomatic, untreated CLL, to evaluate clinical outcomes. Sixty patients with B-CLL received 6 monthly courses of fludarabine (25 mg/m(2) for 5 days) followed by 4 weekly doses of rituximab (375 mg/m(2)). RESULTS: On the basis of National Cancer Institute criteria, 47 of 60 patients (78%) achieved a complete remission, 9 of 60 patients (15%) achieved a partial remission, and 4 of 60 patients (7%) had no response or progressive disease. It is noteworthy that the patients experienced a long progression-free survival (PFS) from treatment (68% at 3 yrs). A significantly shorter PFS was observed in ZAP-70-positive patients (25% vs. 100% at 3 yrs; P = 0.00005), in CD38-positive patients (18% vs. 91% at 3 yrs; P = 0.0002), and in patients who had more minimal residual disease (36% vs. 77% at 2.5 yrs; P = 0.001). CONCLUSIONS: With the addition of rituximab to fludarabine, improved clinical outcomes were obtained, and the stratification of patients by using ZAP-70 and CD38 may help clinicians offer more aggressive and/or experimental approaches to the treatment of patients with high-risk B-CLL subtypes.

Adult↗
PubMed2005

Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid.

BACKGROUND: The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). METHODS: Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for > or = 2 months were considered evaluable. RESULTS: Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63-550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone. CONCLUSIONS: Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life.

Acute Disease↗
PubMed2005

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid (RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response.

Binding Sites↗
PubMed2005

Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.

Approximately one third of acute myeloid leukemias (AMLs) are characterized by aberrant cytoplasmic localization of nucleophosmin (NPMc+ AML), consequent to mutations in the NPM putative nucleolar localization signal. These events are mutually exclusive with the major AML-associated chromosomal rearrangements, and are frequently associated with normal karyotype, FLT3 mutations, and multilineage involvement. We report the gene expression profiles of 78 de novo AMLs (72 with normal karyotype; 6 without major chromosomal abnormalities) that were characterized for the subcellular localization and mutation status of NPM. Unsupervised clustering clearly separated NPMc+ from NPMc- AMLs, regardless of the presence of FLT3 mutations or non-major chromosomal rearrangements, supporting the concept that NPMc+ AML represents a distinct entity. The molecular signature of NPMc+ AML includes up-regulation of several genes putatively involved in the maintenance of a stem-cell phenotype, suggesting that NPMc+ AML may derive from a multipotent hematopoietic progenitor.

Acute Disease↗
PubMed2005

Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo.

The acute promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) fusion product recruits histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities on retinoic acid (RA)-target promoters causing their silencing and differentiation block. RA treatment induces epigenetic modifications at its target loci and restores myeloid differentiation of APL blasts. Using RA-sensitive and RA-resistant APL cell lines and primary blasts, we addressed the functional relevance of the aberrant methylation status at the RA-target promoter RARbeta2 and the mechanism by which methylation is reversed by RA. RA decreased DNMT expression and activity, which correlated with demethylation at specific sites on RARbeta2 promoter/exon-1, and the ability of APL blasts to differentiate in vitro and in vivo. None of these events occurred in an RA-resistant APL cell line containing a PML-RARalpha defective for ligand binding. The specific contribution of the HDAC and DNMT pathways to the response of APL cells to RA was also tested by inhibiting these enzymatic activities with TSA and/or 5-azacytidine. In RA-responsive and RA-resistant APL blasts, TSA and 5-azacytidine induced specific changes on the chromatin state at RA-target sites, increased the RA effect on promoter activity, endogenous RA-target gene expression and differentiation. These results extend the rationale for chromatin-targeted treatment in APL and RA-resistant leukemias.

Blast Crisis↗
PubMed2005

GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children.

The role of all-trans retinoic acid (ATRA) in pediatric acute promyelocytic leukemia (APL) is the topic of several ongoing studies. The results of the Italian pediatric experience with the multicentric Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)-Italian Pediatric Hematology and Oncology Group (AIEOP) "AIDA" (ATRA and idarubicin) trial are presented. Of the 983 patients with APL enrolled in this protocol between January 1993 and June 2000, 124 (13%) had younger than 18 years. Treatment consisted of ATRA and idarubicin induction followed by 3 polychemotherapy consolidation courses. Molecular response by reverse transcriptase-polymerase chain reaction (RT-PCR) was assessed after consolidation and patients who were PCR- were randomized for different maintenances. One hundred and seven children were eligible and evaluable for induction: 103 (96%) achieved a hematologically complete remission. Overt ATRA syndrome was observed in 2 patients and pseudotumor cerebri was observed in 10 patients. Ninety-four patients were evaluable for RT-PCR analysis at the end of consolidation: 91 (97%) proved PCR+ and 3 PCR-. The overall survival and event-free survival (EFS) are 89% (95% confidence interval [c.i.]: 83%-95%) and 76% (c.i.: 65%-85%), respectively, at more than 10 years. A white blood cell (WBC) count at diagnosis of greater than 10 x 10(9)/L had a significant impact on EFS (59% vs 83% at 10 years). These results highlight the efficacy and feasibility of the AIDA protocol in the pediatric APL population.

Adolescent↗
PubMed2005

Apoptosis and immaturity in acute myeloid leukemia.

The primary cause of treatment failures in acute myeloid leukemia (AML) is the emergence of both resistant disease and early relapse. Among the most frequent agents of these phenomena are defects in the mitochondrial-mediated apoptotic pathway. This pathway is regulated by bcl-2 family of anti-apoptotic (bcl-2, bcl-xl, mcl-1) and pro-apoptotic proteins (bax, bad, bak). In particular, bcl-2 dimerizes with several members of bcl-2 family of proteins, altering the threshold of cell death. The flow cytometric quantitative measurement of bcl-2 and bax expression for the determination of bax/bcl-2 ratio provided crucial clinical information in AML: in our hands, lower bax/bcl-2 ratio conferred a very poor prognosis with decreased rates of complete remission (CR) and overall survival (OS). Moreover, striking correlations were found between lower bax/bcl-2 ratio and higher progenitor marker expression, such as CD34, CD117 and CD133 antigens, confirming the link between this apoptotic index and the maturation pathways. However, the capacity of bax/bcl-2 ratio to clearly identify patients with different prognosis with regard to CR and OS within the CD34+, CD117+ and CD133+ subgroups implies that other mechanisms, such as proliferation and/or cell cycle dysregulation may be involved to explain its clinical significance. Finally, small molecules that target both the receptor- and mitochondrial-mediated pathway of apoptosis are providing encouraging results in patients with relapsed and/or refractory disease (i.e. CDDOMe, bcl-2 antisense oligonucleotides, CEP-701, etc), confirming the key role of apoptotic mechanisms on the outcome of AML patients.

Acute Disease↗
PubMed2005

TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL.

BACKGROUND AND OBJECTIVES: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML). DESIGN AND METHODS: TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL). RESULTS: In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression. INTERPRETATION AND CONCLUSIONS: The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.

Acute Disease↗
PubMed2005

Standard practice and controversial issues in front-line therapy of acute promyelocytic leukemia.

In addition to choosing a state-of-the-art regimen including all-transretinoic and anthracycline chemotherapy, modern management of acute promyelocytic leukemia (APL) implies the adoption of appropriate supportive measures, rapid establishment of an accurate genetic diagnosis, correct assessment of response to therapy and evaluation of the risk of disease recurrence by molecular monitoring. However, the general consensus about this overall strategy for APL treatment still leaves room for a number of controversial issues. In the present article, we review the current standard practice and controversial issues in the treatment of patients with newly diagnosed APL, including the management of special situations such as elderly patients, children and pregnant women.

Adolescent↗
PubMed2005

Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence.

Recent studies have demonstrated the beneficial effects of arsenic trioxide (ATO) in the treatment of relapsed acute promyelocytic leukemia (APL). The aim of this review is to discuss the role of ATO in the management of APL. Based on the available clinical evidence, a tentative algorithm is proposed for the treatment of patients who relapse after or are refractory to all trans-retinoic acid-based therapy. Other opportunities for the use of ATO in front-line treatment of APL are also discussed, especially its potential use in patients at high risk of relapse and in those with contraindications to chemotherapy or in whom the amount of chemotherapy should be reduced.

Arsenic Trioxide↗
PubMed2004

Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells.

Patients with myeloid malignancies and either the 3q21q26 syndrome or t(1;3)(p36;q21) have been reported to share similar clinicopathological features and a common molecular mechanism for leukemogenesis. Overexpression of MDS1/EVI1 (3q26) or MEL1/PRDM16 (1p36), both members of the PR-domain family, has been directly implicated in the malignant transformation of this subset of neoplasias. The breakpoints in both entities are outside the genes, and the 3q21 region, where RPN1 is located, seems to act as an enhancer. MEL1 has been reported to be expressed in leukemia cells with t(1;3) and in the normal uterus and fetal kidney, but neither in bone marrow (BM) nor in other tissues, suggesting that this gene is specific to t(1;3)-positive MDS/AML. We report the molecular characterization of a t(1;3)(p36;q21) in a patient with MDS (RAEB-2). In contrast to previous studies, we demonstrate that MEL1, the PR-containing form, and MEL1S, the PR-lacking form, are widely expressed in normal tissues, including BM. The clinicopathological features and the breakpoint on 1p36 are different from cases previously described, and MEL1 is not overexpressed, suggesting a heterogeneity in myeloid neoplasias with t(1;3).

Aged↗
PubMed2004

Clinico-biological features and outcome of acute promyelocytic leukemia patients with persistent polymerase chain reaction-detectable disease after the AIDA front-line induction and consolidation therapy.

BACKGROUND AND OBJECTIVES: Front line treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and chemotherapy (CHT) results in molecular remission in approximately 95% of patients tested after consolidation. The small fraction of patients with persistence of molecular disease (i.e. those in whom polymerase chain reaction (PCR) is positive for PML/RARalpha) after such therapy are thought to have a dismal prognosis but has not yet been investigated in detail. DESIGN AND METHODS: We analyzed the clinico-biological features at presentation of APL patients who showed PCR-detectable residual disease and compared them to those of patients achieving molecular remission after AIDA induction and consolidation. Furthermore, we report the outcome of patients with molecularly persistent disease treated with salvage therapy. RESULTS: Patients attaining molecular remission (n=650) and patients who tested PCR+ve at the end of consolidation (n=23) were not statistically significantly different as regards median age, white cell and platelet counts, morphologic subtype (M3 or M3v), fibrinogen levels or PML/RARalpha transcript type. As to treatment outcome after salvage therapy, 7 patients were treated before morphologic relapse [3 with chemotherapy and autologous stem cell transplantation (SCT) and 4 with allogeneic SCT], and are alive after 64-118 months. Of 16 patients treated at the time of morphologic relapse, only 2 patients are alive, both of whom received an allogeneic SCT. INTERPRETATION AND CONCLUSIONS: Our findings indicate that APL patients who are molecularly resistant to the AIDA protocol have no distinguishing features at presentation. Their outcome suggests the need for early therapeutic intervention with aggressive treatment prior to the occurrence of hematologic relapse.

Adolescent↗