Publications (22)112.13 Total impact
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Article: Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity.
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ABSTRACT: Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided.Expert Opinion on Investigational Drugs 12/2009; 18(12):1939-46. · 5.27 Impact Factor -
Article: Conservative surgical management of stage IA endometrial carcinoma for fertility preservation.
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ABSTRACT: To describe an innovative method to preserve fertility in young women with stage IA endometrial cancer with use of hysteroscopic resection followed by administration of 160 mg of megestrol acetate. Prospective study. Division of Gynecologic Oncology, Catholic University of the Sacred Heart, and the Endoscopic Gynecologic Unit, Nuova Villa Claudia, Rome, Italy. Six young patients with stage IA endometrial cancer. Conservative resectoscopic treatment using a three-step technique in which each step is characterized by a pathologic analysis: the removal of the tumor (step 1), the removal of the endometrium adjacent to the tumor (step 2), and the removal of the myometrium underlying the tumor (step 3). Therapy of stage IA endometrial cancer and pregnancy. The conservative surgery was effective because results of transvaginal ultrasound examination and diagnostic hysteroscopy with target biopsies at 3, 6, 9, and 12 months after surgery were negative for atypia or malignancy. Moreover, four out of six patients (66%) achieved childbearing. This method, under a close postsurgical follow-up, might represent a novel therapeutic option for those women with stage IA endometrial cancer who wish to preserve fertility.Fertility and sterility 09/2009; 93(4):1286-9. · 3.97 Impact Factor -
Article: Review role of topotecan in gynaecological cancers: current indications and perspectives.
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ABSTRACT: Ovarian cancer is the fourth cause of death from gynaecological cancer and cervical cancer is the first in women <45 years old in developing countries. The aim of this article is to review the role of topotecan (Hycamtin), a semi-synthetic alkaloid derivative of camptothecin, in ovarian and cervical cancer in monotherapy and in combination. This article reviews the mechanism of action, pharmacokinetics, toxicity and efficacy of topotecan. The paper also reports the principal phases II and III studies of topotecan in advanced or recurrent ovarian and cervical cancer. Topotecan (Hycamtin), currently indicated for the treatment of relapsed ovarian cancer, has demonstrated activity both in platinum-sensitive and in platinum-resistant disease. The combination cisplatin-topotecan for the treatment of advanced and recurrent cervical cancer has demonstrated a clinical benefit in terms of response rate, overall survival and progression free survival. Haematological toxicity of topotecan also is easy to manage and not cumulative, especially with the weekly scheduled recently introduced in clinical practice. Topotecan (Hycamtin) will continue to play a role in the treatment of advanced ovarian and cervical cancer, in monotherapy or in combination with other cytotoxic agents.Critical reviews in oncology/hematology 09/2009; 74(3):163-74. · 5.27 Impact Factor -
Article: Cyclin E correlates with manganese superoxide dismutase expression and predicts survival in early breast cancer patients receiving adjuvant epirubicin-based chemotherapy.
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ABSTRACT: Anthracycline-based chemotherapy represents a milestone in the treatment of breast cancer. We previously demonstrated in an in vitro model that cyclin E overexpression is associated with increased expression of manganese superoxide dismutase (MnSOD) and resistance to doxorubicin. In the present study, immunohistochemical expression of cyclin E and MnSOD was evaluated in 134 early breast cancer patients receiving adjuvant epirubicin-based chemotherapy regimens containing epirubicin. Both parameters were correlated with the available clinicopathological parameters and with the outcome of patients. Overexpression of cyclin E and MnSOD was detected in 46 (34.3%) and 56 (41.8%) patients, respectively, and expression levels of the two proteins were related. Disease-free and alive patients displayed a lower mean percentage of cyclin E-expressing cells than relapsed and dead patients, respectively. Kaplan-Meier survival analysis demonstrated a significant separation between high versus low cyclin E-expressing tumors in terms of overall survival (P = 0.038 by log-rank). Similar results were obtained considering the subset of node-negative patients separately. No significant relationship with patient outcome was observed for MnSOD expression levels. At multivariate analysis cyclin E failed to demonstrate an independent prognostic value. In conclusion, the results of the present study support previous evidence that increased cyclin E expression is associated with higher MnSOD expression levels and poorer outcome, at least as evaluated in terms of overall survival. Further studies are warranted to evaluate the usefulness of cyclin E as a prognostic marker to identify breast cancer patients at higher risk of death from the disease when treated with adjuvant anthracycline-based therapy.Cancer Science 04/2009; 100(6):1026-33. · 3.33 Impact Factor -
Article: The retinoblastoma family member pRb2/p130 is an independent predictor of survival in human soft tissue sarcomas.
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ABSTRACT: pRb2/p130, a member of the Retinoblastoma gene family, has been shown to be a powerful prognostic factor in several malignancies. We sought to evaluate pRb2/p130 protein expression and its clinical effect in patients affected with soft tissue sarcomas (STS). Expression of pRb2/p130 was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded sections in 41 STSs. Results obtained were correlated with clinicopathologic variables and disease-free and overall survival (OS) in univariate and multivariate analysis. Expression of pRb2/p130 was diminished in 25 (61%) tumors, whereas the remaining ones (39%) were classified as high expressors. No correlation between pRb2/p130 expression and clinicopathologic variables was observed. However, a direct relationship between pRb2/p130 expression and clinical outcome of the patients was found in the subgroup of nonmetastatic tumors (n = 31). In univariate analysis, reduced pRb2/p130 expression was a negative prognostic factor and correlated with shorter disease-free survival (P = 0.021) and OS (P = 0.017) survival. In multivariate analysis, reduced pRb2/p130 expression was confirmed to be an independent predictor of shorter OS when considered together with tumor stage and grading (risk ratio, 7.893; confidence interval, 1.618-38.509; P = 0.011). This study shows for the first time the potential prognostic value of pRb2/130 expression evaluated on formalin-fixed, paraffin-embedded sections in STSs patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with nonmetastatic STSs and, therefore, may represent a new prognostic marker.Clinical Cancer Research 09/2008; 14(15):4775-9. · 7.74 Impact Factor -
Chapter: Molecular Genetics of Cervical Cancer
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ABSTRACT: The carcinoma of the uterine cervix is the second most common cancer among women worldwide, with its higher incidence in developing countries (1). Strong clinical and experimental evidence demonstrated that the high-risk (HR) types of human papilloma virus (HPV) play a central role in causing cervical cancer, although a role of multiple risk factors has been suggested too. Not only does the epidemiological data indicate the criteria of causality on HPV and cervical cancer, but also there are several studies that identified the viral transforming genes, and their mode of action supports a model of multistep carcinogenesis. It is generally accepted that the development of invasive cervical cancer from intraepithelial neoplasia (cervical intraepithelial neoplasia [CIN] 1-2/3) involves molecular changes and therefore is a preventable if detected and treated early. The vast majority of low-grade squamous intraepithelial lesions (LSILs) regress spontaneously and it is estimated that about 10–20% of high-grade SILs (HSILs) are at risk of progressing into invasive cancer.12/2006: pages 113-123; -
Article: p27kip1 overexpression promotes paclitaxel-induced apoptosis in pRb-defective SaOs-2 cells.
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ABSTRACT: p27kip1 is a cyclin-dependent kinase (CDK) inhibitor, which controls several cellular processes in strict collaboration with pRb. We evaluated the role of p27kip1 in paclitaxel-induced apoptosis in the pRb-defective SaOs-2 cells. Following 48 h of exposure of SaOs-2 cells to 100 nM paclitaxel, we observed an increase in p27kip1 expression caused by the decrease of the ubiquitin-proteasome activity. Such increase was not observed in SaOs-2 cells treated with the caspase inhibitors Z-VAD-FMK, suggesting that p27kip1 enhancement at 48 h is strictly related to apoptosis. Finally, we demonstrated that SaOs-2 cells transiently overexpressing the p27kip1 protein are more susceptible to paclitaxel-induced apoptosis than SaOs-2 cells transiently transfected with the empty vector. Indeed, after 48 h of paclitaxel treatment, 41.8% of SaOs-2 cells transiently transfected with a pcDNA3-p27kip1 construct were Annexin V-positive compared to 30.6% of SaOs-2 cells transfected with the empty vector (P < 0.05). In conclusion, we demonstrated that transfection of the pRb-defective SaOs-2 cells with the p27kip1 gene via plasmid increases their susceptibility to paclitaxel-induced apoptosis. The promoting effect of p27kip1 overexpression on apoptosis makes p27kip1 and proteasomal inhibitors interesting tools for therapy in patients with pRb-defective cancers.Journal of Cellular Biochemistry 08/2006; 98(6):1645-52. · 2.87 Impact Factor -
Article: Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas
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ABSTRACT: The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto-oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness. © 1995 Wiley-Liss, Inc.International Journal of Cancer 07/2006; 64(4):280 - 285. · 5.44 Impact Factor -
Chapter: Role of the Retinoblastoma Family in Cell Cycle Progression and Growth Control
01/2005: pages 607 - 634; , ISBN: 9780471656432 -
Article: pRb2/p130 decreases sensitivity to apoptosis induced by camptothecin and doxorubicin but not by taxol.
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ABSTRACT: In addition to their original function as cell cycle regulators, retinoblastoma (Rb) family members were recently reported to modulate the sensitivity of cancer cells to chemotherapeutic agents. The purpose of this study is to investigate the possible role of pRb2/p130 in the sensitivity of ovarian cancer to camptothecin, doxorubicin, and taxol. pRb2/p130 was overexpressed in the CAOV-3 ovarian cancer cell line, and the effect of pRb2/p130 overexpression on sensitivity to apoptosis trigged by IC(50) doses of different drugs was evaluated by various methods, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and Western blot analyses. The results reported in this study support the conclusion that overexpression of pRb2/p130 in the CAOV-3 ovarian cancer cell line lacking wild-type p53 is able to inhibit apoptosis triggered by camptothecin and doxorubicin through the c-Jun NH(2)-terminal kinase signaling transduction pathway. Conversely, taxol-induced cell death is not influenced by the pRb2/p130 protein level. A careful analysis of pRb2/p130 expression in tumor specimens could help to identify the best clinical protocol to be used for each patient, improving efficacy and tolerance and therefore offering additional progress in the treatment of advanced ovarian cancer.Clinical Cancer Research 01/2005; 10(23):8085-93. · 7.74 Impact Factor -
Article: Frequent loss of pRb2/p130 in human ovarian carcinoma.
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ABSTRACT: RB2/p130, a member of the retinoblastoma gene family, maps to human chromosome 16q12.2, a region in which deletions have been found in several human neoplasms including breast, prostatic, and ovarian carcinoma. We sought to evaluate pRb2/p130 protein expression and function in ovarian carcinoma. pRb2/p130 expression was detected by immunohistochemical and Western blot analyses in 45 primary ovarian carcinoma samples. Immunohistochemical analysis revealed loss or decrease of pRb2/p130 expression in 18 cases (40%). pRb2/p130 expression was mostly nuclear and inversely correlated to the tumor grade (P < 0.05). Western blot analysis correlated with immunohistochemical expression. Reverse transcription-PCR followed by Southern blot analysis was performed on a representative set of 20 ovarian carcinomas. RB2/p130 mRNA levels were consistent with protein expression. We found a significant increase in the percentage of G(1)-phase-arrested cells in CAOV3 and A2780 ovarian carcinoma cell lines after transduction with an adenovirus carrying the RB2/p130 gene (Ad-CMV-RB2/p130). These data indicate that loss or decrease of pRb2/p130 expression is a frequent event in ovarian carcinoma and is regulated mostly at the transcriptional level. Moreover, pRb2/p130 overexpression is able to arrest cell growth in ovarian carcinoma cells, suggesting the putative role of pRb2/p130 as a tumor suppressor in this malignancy.Clinical Cancer Research 06/2004; 10(9):3098-103. · 7.74 Impact Factor -
Article: The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity.
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ABSTRACT: Cytotoxicity of methylating agents is caused mostly by methylation of the O6 position of guanine in DNA to form O6-methylguanine (O6-meG). O6-meG can direct misincorporation of thymine during replication, generating O6-meG:T mismatches. Recognition of these mispairs by the mismatch repair (MMR) system leads to cell cycle arrest and apoptosis. MMR also modulates sensitivity to other antitumor drugs. The base excision repair (BER) enzyme MED1 (also known as MBD4) interacts with the MMR protein MLH1. MED1 was found to exhibit thymine glycosylase activity on O6-meG:T mismatches. To examine the biological significance of this activity, we generated mice with targeted inactivation of the Med1 gene and prepared mouse embryonic fibroblasts (MEF) with different Med1 genotype. Unlike wild-type and heterozygous cultures, Med1-/- MEF failed to undergo G2-M cell cycle arrest and apoptosis upon treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Similar results were obtained with platinum compounds' 5-fluorouracil and irinotecan. As is the case with MMR-defective cells, resistance of Med1-/- MEF to MNNG was due to a tolerance mechanism because DNA damage accumulated but did not elicit checkpoint activation. Interestingly, steady state amounts of several MMR proteins are reduced in Med1-/- MEF, in comparison with Med1+/+ and Med1+/- MEF. We conclude that MED1 has an additional role in DNA damage response to antitumor agents and is associated with integrity of the MMR system. MED1 defects (much like MMR defects) may impair cell cycle arrest and apoptosis induced by DNA damage.Proceedings of the National Academy of Sciences 01/2004; 100(25):15071-6. · 9.68 Impact Factor -
Article: Frequent loss of expression of the cyclin-dependent kinase inhibitor p27(Kip1) in estrogen-related Endometrial adenocarcinomas.
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ABSTRACT: p27(Kip1) is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Low levels of p27 are associated with poor prognosis in a variety of gynecological tumors, including breast, ovarian, and cervical carcinomas. The role of p27 in endometrial cancer remains controversial. In the present study, p27 protein expression was investigated by immunohistochemistry in a series of 217 endometrial adenocarcinomas and, where present, in synchronous normal endometrium, simple and complex hyperplasia (with or without atypia), and cystic atrophy. The relationship between p27 expression and clinical outcome was also evaluated. Immunohistochemical analysis revealed a significant loss of p27 expression from normal (33%) through hyperplastic endometrium (50%) to endometrial adenocarcinomas (71%; P </= 0.001). In addition to nuclear staining, cytoplasmic localization of p27 was noted in 193 (91%) of 217 specimens examined. When the clinical outcome of the patients was evaluated in relation to p27 status, we found no significant correlation between the presence of p27 staining and clinicopathological parameters or survival. These data indicate that p27 expression could progressively decrease from normal endometrium through hyperplastic endometrium to invasive endometrial carcinomas, suggesting that loss of this tumor suppressor may represent a novel and distinct molecular alteration involved in estrogen-related endometrial adenocarcinomas (type I). Despite the suggested role of the p27 protein in determining the prognosis of several human tumors, it was not found to be a predictor of clinical outcome in this large group of patients with endometrial cancer.Clinical Cancer Research 11/2003; 9(14):5332-8. · 7.74 Impact Factor -
Article: HMGA1 protein over-expression is a frequent feature of epithelial ovarian carcinomas.
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ABSTRACT: High mobility group A 1 (HMGA1) proteins are chromatinic factors, which are absent or expressed at very low levels in normal adult tissues, while they are over-expressed in several human malignant tumors. In this study, HMGA1 protein expression was investigated by immunohistochemistry in a series of 44 epithelial ovarian specimens, which included four normal ovarian tissues, 29 primary invasive carcinomas, one metastatic ovarian tumor and 10 low malignant potential (LMP) tumors. HMGA1 staining was not detected in normal ovarian surface epithelium, which is the area from which ovarian adenocarcinoma frequently arises. HMGA1 proteins were expressed at low levels in some LMP tumors, whereas they were present in abundance in most of the primary ovarian adenocarcinomas. RT-PCR and western blot analysis correlated with immunohistochemical data. We demonstrated that the suppression of HMGA1 protein synthesis by an adenovirus carrying the HMGA1 gene in antisense orientation (Ad-Yas-GFP) inhibited the growth of two human ovarian carcinoma cell lines (OVCAR-5 and OVCAR-8). These results confirm HMGA1 over-expression as a general feature of human malignant neoplasias, including ovarian cancer and suggest that suppression of HMGA1 protein synthesis by an antisense adenoviral vector may represent a new and promising gene therapy for the treatment of ovarian cancer.Carcinogenesis 08/2003; 24(7):1191-8. · 5.70 Impact Factor -
Article: Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27.
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ABSTRACT: In an effort to identify tumor suppressor gene(s) associated with the frequent loss of heterozygosity observed on chromosome 6q25-q27, we constructed a contig derived from the sequences of bacterial artificial chromosomeP1 bacteriophage artificial chromosome clones defined by the genetic interval D6S1581-D6S1579-D6S305-D6S1599-D6S1008. Sequence analysis of this contig found it to contain eight known genes, including the complete genomic structure of the Parkin gene. Loss of heterozygosity (LOH) analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%). Both loci exhibited the highest frequencies of LOH in this study and are each located within the Parkin genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the Parkin gene appeared to be down-regulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of two truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in the lung adenocarcinoma cell lines Calu-3 and H-1573, supports the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of Parkin in these samples. These data suggest that the LOH observed at chromosome 6q25-q26 may contribute to the initiation andor progression of cancer by inactivating or reducing the expression of the Parkin gene. Because Parkin maps to FRA6E, one of the most active common fragile sites in the human genome, it represents another example of a large tumor suppressor gene, like FHIT and WWOX, located at a common fragile site.Proceedings of the National Academy of Sciences 06/2003; 100(10):5956-61. · 9.68 Impact Factor -
Article: Loss of pRb2/p130 expression is associated with unfavorable clinical outcome in lung cancer.
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ABSTRACT: Altered expression of cell cycle regulators represents a frequent event in both small cell and non-small cell lung cancer (NSCLC). Despite several studies that reported involvement of tumor suppressor genes, such as p53 and pRb, in the development and progression of lung cancer, contrasting opinions exist about the prognostic role of this protein in this neoplasm. We developed an immunohistochemical assay suitable for the detection of pRb2/p130, the last discovered member of the retinoblastoma gene family, on formalin-fixed and paraffin-embedded sections. We evaluated the immunohistochemical expression of pRb2/p130 in 135 lung cancer specimens, and performed Western blot analysis in a subset of 30 corresponding tumor lysates. A high correlation between immunohistochemical data and Western blot results (P = 0.0004) was found. We statistically analyzed the relationship between overall survival (OS) time and pRb2/p130 expression according to the different histological types in 105 patients. We did not find any correlation between pRb2/p130 expression and OS in small cell lung cancers, whereas in NSCLCs a direct relationship between pRb2 and OS was found in both adenocarcinoma (P = 0.0002) and squamous cell carcinoma (P = 0.0002) histotypes. According to univariate analysis, pRb2/p130 was a prognostic factor of which the lost or reduced expression correlated with a shorter OS (P < 0.0000). At multivariate analysis, pRb2/p130 expression was an independent predictor of OS (P = 0.0001) when considered together with histotype. This study demonstrates for the first time the potential independent prognostic value of pRb2/p130 expression on formalin-fixed, paraffin-embedded sections from lung cancer patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with NSCLC and, therefore, may represent a new prognostic marker.Clinical Cancer Research 12/2002; 8(12):3850-6. · 7.74 Impact Factor -
Article: pRb2/p130 promotes radiation-induced cell death in the glioblastoma cell line HJC12 by p73 upregulation and Bcl-2 downregulation.
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ABSTRACT: This study shows that in the glioblastoma hamster cell line HJC12 the retinoblastoma family member pRb2/p130 enhances gamma-radiation-induced cell death. In HJC12 cells the tetracycline-regulated expression of pRb2/p130 increased the percentage of gamma-radiation-induced apoptotic cells from 27 to 47%. pRb2/p130 overexpression was associated with the downregulation of the anti-apoptotic factor Bcl-2 and the upregulation of the steady-state protein levels of the pro-apoptotic transcription factor p73. In particular, RT-PCR showed a significant increase in the expression of the p73delta isoform when pRb2/p130 was overexpressed. The ability of pRb2/p130 to modulate apoptosis was not associated with its role in mediating G0/G1 arrest during cell cycle progression. Our data suggest a role for pRb2/p130 in glioblastoma gamma-radiation-induced cell death, indicating that the antitumoral action of pRb2/p130 can regulate both inhibition of cell cycle progression and induction of cell death.Oncogene 09/2002; 21(38):5897-905. · 6.37 Impact Factor -
Article: High cyclin‐dependent kinase inhibitors in Bcl‐2 and Bcl‐xL‐expressing CD34+‐proliferating haematopoietic progenitors
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ABSTRACT: We have previously described the isolation of primitive, slow-proliferating progenitors from normal, circulating CD34+ cells by using the fluorescent dye 5-6-carboxyfluorescein diacetate succinimidyl ester (CFDA-SE). CFDA-SEbright (primitive) and CFDA-SEdim (differentiating) cells were isolated following cytokine stimulation on the basis of their different proliferation rates. In the present work we analysed the expression levels of a number of proteins involved with differentiation, proliferation and survival/apoptosis in CFDA-SEbright/CD34+/slow-proliferating cells that were previously defined as progenitors capable of differentiating into different lineages. The aim of this work was to gain a better understanding of our model system in order to define some of the important parameters that regulate differentiation in haematopoietic progenitors. GATA-1 and PU.1 RNA levels were similar in freshly isolated (d 0) CD34+ and in CFDA-SEbright (bright) cells, whereas they increased in CFDA-SEdim (dim) cells. Accordingly, Nm23 was expressed at higher levels in bright cells. Moreover, bright cells had higher p21WAF1/CIP1, p27KIP1 and p16Ink4 protein levels than dim cells. Consistently, Cdc2 and Cdk2 kinase activity was much higher in the dim than in the slower proliferating bright cells. C-myc and p53 levels were higher in bright cells than in d 0 CD34+ and dim cells, and so was Bcl-xL, which followed the trend we have previously described for Bcl-2. Thus, bright cells, despite having a higher proliferation rate than the starting d 0 CD34+ population, have strikingly elevated levels of cyclin-dependent kinase inhibitors, which are likely to also act as inhibitors of differentiation.British Journal of Haematology 12/2001; 110(3):654 - 662. · 4.94 Impact Factor -
Article: Analysis of cyclin E and CDK2 in ovarian cancer: Gene amplification and RNA overexpression
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ABSTRACT: Cyclins and their associated kinases (cdks) play a key role in controlling the cell cycle, a process whose disregulation can potentially lead to uncontrolled cell growth and hence to cancer. We have studied the role of both cyclin E and its associated kinase cdk2 in ovarian cancer. Primary, metastatic, recurrent and benign ovarian tumors were screened for cyclin E and cdk2 gene amplification. Cyclin E was shown to be amplified in 21% and cdk2 in 6.4% of the cases analyzed. Cyclin E and cdk2 RNA expression levels were determined by semi-quantitative RT-PCR analysis in a partially overlapping series of samples and compared to the expression levels of normal ovarian surface epithelial cells. Cyclin E RNA was overexpressed in 29.5% and cdk2 in 6.5% of ovarian tumors tested. We determined that in most cases gene amplification leads to higher RNA levels for cyclin E and that the overall levels of cyclin E and cdk2 RNA were correlated. We hypothesize that cyclin E and cdk2 are, in part co-regulated and that they may concur to ovarian tumor development. Int. J. Cancer 75:34–39, 1998.© 1998 Wiley-Liss, Inc.International Journal of Cancer 12/1998; 75(1):34 - 39. · 5.44 Impact Factor -
Article: Altered expression of cyclin D1 and CDK4 genes in ovarian carcinomas
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ABSTRACT: We analyzed the expression and amplification of cyclin D1 and CDK4 genes in ovarian carcinomas. Northern blot analysis revealed overexpression of cyclin D1 in 12 of 65 (18%) ovarian carcinomas while CDK4 was overexpressed in 7 of 48 cases (14%). None of the tumors showed amplification of any of the 2 genes. Overexpression of cyclin D1 and CDK4 transcripts was correlated, suggesting a role of both genes in altered growth control of ovarian cancer cells. Elevated levels of cyclin D1 were significantly associated with a well-moderately differentiated grade (G1-G2) (p < 0.005). No significant association was found between cyclin D1 expression and estrogen receptor, progesterone and epidermal growth factor receptor content. Cyclin D1 expression does not appear to be associated with clinical outcome in human ovarian cancer, although a longer follow-up period and screening of other molecules involved in the same pathway would be necessary to assess this hypothesis. Int. J. Cancer 74:390–395, 1997. © 1997 Wiley-Liss, Inc.International Journal of Cancer 12/1998; 74(4):390 - 395. · 5.44 Impact Factor
Top co-authors
Top Journals
Institutions
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2004–2008
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Temple University
- College of Science and Technology
Philadelphia, PA, USA
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2006
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Istituto Regina Elena - Istituti Fisioterapici Ospitalieri
Roma, Latium, Italy
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2005
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Dana-Farber Cancer Institute
Boston, MA, USA
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2001–2005
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Thomas Jefferson University
- Department of Pathology, Anatomy & Cell Biology
Philadelphia, PA, USA
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2002–2003
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Jefferson College
Hillsboro, MO, USA -
Second University of Naples
Caserta, Campania, Italy
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1998
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The Catholic University of America
Washington, D. C., DC, USA
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