Table of Contents
- Retinoblastoma gene product and P21 (WAF1, CIP1) protein expression in non Hodgkin's lymphomas: a multivariate survival analysis.
- Modified order of allelic replication in lymphoma patients at different disease stages.
- Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia.
- Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding.
- The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression.
- Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia.
- Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines.
CancerMail from the National Cancer InstituteRetinoblastoma Gene (RB) - September 2001
1
UI - 21319829
AU - Korkolopoulou PA; Angelopoulou MK; Kontopidou FN; Patsouris EV; Christodoulou PN; Kittas CN; Davaris P; Pangalis GA
TI - Retinoblastoma gene product and P21 (WAF1, CIP1) protein expression in non Hodgkin's lymphomas: a multivariate survival analysis.
SO - Leuk Lymphoma 2001 Feb;40(5-6):647-58
AD - Department of Pathology, University of Athens, Greece.
We evaluated immunohistochemically the expression of two negative regulators of the cell cycle, namely retinoblastoma gene product (pRb) and WAF1/Cip1 gene product (p21), in paraffin sections from 93 patients with non-Hodgkin's lymphomas (NHL) and related it to clinicopathological parameters, proliferative fraction, p53 expression and survival. Patients were followed until death (n=33) or for an average of 52 months (60-160). Rb labelling index (LI) increased with malignancy grade and proliferative activity but was unrelated to other clinicopathological parameters. In 33% of cases, especially those of the aggressive groups, we observed diminished pRb expression (i.e. low pRb/Ki-67 ratio). p21 expression on the other hand correlated only with histological grade, Rb LI and p53 LI. In multivariate analysis, Rb LI was a negative predictor of disease-free survival but was linked to a higher probability of complete response. However, diminished pRb expression as well as p21 expression were not statistically significant prognostic indicators. Our results suggest that pRb as a cell cycle related molecule may play an important role in determining prognosis and therapeutic response in NHL patients.
2
UI - 21261633
AU - Amiel A; Elis A; Blumenthal D; Gaber E; Fejgin MD; Dubinsky R; Lishner M
TI - Modified order of allelic replication in lymphoma patients at different disease stages.
SO - Cancer Genet Cytogenet 2001 Mar;125(2):156-60
AD - Genetic Institute and Department of Medicine and Hematology, Meir Hospital, Sapir Medical Center, Kfar-Saba, Israel. alizaamiel@hotmail.com
Asynchronous replication of homologous loci was reported in lymphocytes of patients with lymphoma, ovarian and renal cancer as well as in lymphocytes of patients with premalignant conditions, for example, essential mixed cryoglobulinemia associated with hepatitis C virus and in monoclonal gammopathy of unknown significance. In the present study we evaluated the replication pattern in lymphocytes of four groups of patients with intermediate grade of non-Hodgkin lymphoma at various stages of their disease: 1) at diagnosis; 2) during cytotoxic treatment; 3) in remission; and 4) in relapse. A significantly higher proportion of the asynchronous pattern of replication at diagnosis, during cytotoxic treatment, and in relapse was noted as compared to healthy controls and to patients who achieved remission of their lymphoma. Also, the frequency of the two doublets (DD) pattern in every group studied was significantly lower than in the controls. If our findings can be confirmed in larger, long-term prospective studies, it may allow the use of a simple and inexpensive tool to closely observe patients with lymphoma who are at high risk for relapse.
3
UI - 21394127
AU - Diaz-Cano SJ; de Miguel M; Blanes A; Tashjian R; Wolfe HJ
TI - Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia.
SO - J Clin Endocrinol Metab 2001 Aug;86(8):3948-57
AD - Department of Pathology, Tufts University-New England Medical Center, Boston, Massachusetts 02111, USA. s.j.diaz-cano@mds.qmw.ac.uk
C-cell hyperplasias are normally multifocal in multiple endocrine neoplasia type 2A. We compared clonality, microsatellite pattern of tumor suppressor genes, and cellular kinetics of C-cell hyperplasia foci in each thyroid lobe. We selected 11 females from multiple endocrine neoplasia type 2A kindred treated with thyroidectomy due to hypercalcitoninemia. C-cell hyperplasia foci were microdissected for DNA extraction to analyze the methylation pattern of androgen receptor alleles and microsatellite regions (TP53, RB1, WT1, and NF1). Consecutive sections were selected for MIB-1, pRB1, p53, Mdm-2, and p21WAF1 immunostaining, DNA content analysis, and in situ end labeling. Appropriate tissue controls were run. Only two patients had medullary thyroid carcinoma foci. Nine informative C-cell hyperplasia patients showed germline point mutation in RET, eight of them with the same androgen receptor allele preferentially methylated in both lobes. C-cell hyperplasia foci showed heterogeneous DNA deletions revealed by loss of heterozygosity of TP53 (12 of 20), RB1 (6 of 14), and WT1 (4 of 20) and hypodiploid G0/G1 cells (14 of 20), low cellular turnover (MIB-1 index 4.5%, in situ end labeling index 0.03%), and significantly high nuclear area to DNA index ratio. MEN 2A (germline point mutation in RET codon 634) C-cell hyperplasias are monoclonal and genetically heterogeneous and show down-regulated apoptosis, findings consistent with an intraepithelial neoplasia. Concordant X-chromosome inactivation and interstitial gene deletions suggest clone expansions of precursors occurring at a point in embryonic development before divergence of each thyroid lobe and may represent a paradigm for other germline mutations.
4
UI - 21412298
AU - Fan S; Yuan R; Ma YX; Xiong J; Meng Q; Erdos M; Zhao JN; Goldberg ID; Pestell RG; Rosen EM
TI - Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding.
SO - Oncogene 2001 Aug 9;20(35):4827-41
AD - Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York, NY 11040, USA. fan@lij.edu
The tumor suppressor activity of the BRCA1 gene product is due, in part, to functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein. RB binding sites on BRCA1 were identified in the C-terminal BRCT domain (Yarden and Brody, 1999) and in the N-terminus (aa 304-394) (Aprelikova et al., 1999). The N-terminal site contains a consensus RB binding motif, LXCXE (aa 358-362), but the role of this motif in RB binding and BRCA1 functional activity is unclear. In both in vitro and in vivo assays, we found that the BRCA1:RB interaction does not require the BRCA1 LXCXE motif, nor does it require an intact A/B binding pocket of RB. In addition, nuclear co-localization of the endogenous BRCA1 and RB proteins was observed. Over-expression of wild-type BRCA1 (wtBRCA1) did not cause cell cycle arrest but did cause down-regulation of expression of RB, p107, p130, and other proteins (e.g., p300), associated with increased sensitivity to DNA-damaging agents. In contrast, expression of a full-length BRCA1 with an LXCXE inactivating mutation (LXCXE-->RXRXH) failed to down-regulate RB, blocked the down-regulation of RB by wtBRCA1, induced chemoresistance, and abrogated the ability of BRCA1 to mediate tumor growth suppression of DU-145 prostate cancer cells. wtBRCA1-induced chemosensitivity was partially reversed by expression of either Rb or p300 and fully reversed by co-expression of Rb plus p300. Our findings suggest that: (1) disruption of the LXCXE motif within the N-terminal RB binding region alters the biologic function of BRCA1; and (2) over-expression of BRCA1 inhibits the expression of RB and RB family (p107 and p130) proteins.
5
UI - 21361187
AU - Gao J; Richardson DR
TI - The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression.
SO - Blood 2001 Aug 1;98(3):842-50
AD - Iron Metabolism and Chelation Group, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, New South Wales, 2050 Australia.
Some chelators of the pyridoxal isonicotinoyl hydrazone class have antiproliferative activity that is far greater than desferrioxamine (DFO). In this study, DFO was compared with one of the most active chelators (311) on the expression of molecules that play key roles in cell-cycle control. This was vital for understanding the role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclin-dependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased after incubation with DFO, and especially 311, which may be important for explaining the decrease in hyperphosphorylated pRb. Cyclins A and B1 were also decreased after incubation with 311 and, to a lesser extent, DFO. In contrast, cyclin E levels increased. These effects were prevented by presaturating the chelators with Fe. In contrast to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea increased the expression of all cyclins. Hence, the effect of chelators on cyclin expression was not due to their ability to inhibit ribonucleotide reductase. Although chelators induced a marked increase in WAF1 and GADD45 mRNA transcripts, there was no appreciable increase in their protein levels. Failure to translate these cell-cycle inhibitors may contribute to dysregulation of the cell cycle after exposure to chelators. (Blood. 2001;98:842-850)
6
UI - 21421106
AU - Brito-Babapulle V; Baou M; Matutes E; Morilla R; Atkinson S; Catovsky D
TI - Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia.
SO - Br J Haematol 2001 Aug;114(2):327-32
AD - Academic Department of Haematology and Cytogenetics/Institute of Cancer Research, London, UK. vasantha@icr.ac.uk
Deletions of 13q14.3 are well known in several malignancies and are thought to be associated with tumour suppressor function. The RB-1 gene is a tumour suppressor gene, but other loci including D13S319 and D13S25 telomeric to this within 13q14.3 are deleted in B-cell chronic lymphocytic leukaemia (B-CLL), multiple myeloma and non-Hodgkin's lymphoma, with varying clinical significance. The fluorescence in situ hybridization screening of 22 patients with T-prolymphocytic leukaemia (T-PLL) for deletions of 13q14.3 revealed loss of D13S25 in 17 cases (mean 40% range 13-98%), with 11 patients having at least a 20% deletion. Mapping the deletions for the RB-1, D13S319,and D13S25 loci revealed D13S25 as the most frequently deleted marker. However, patients with only the D13S25 deletion had low percentages of cells with the deletion (12-13%), suggesting that loss of D13S25 on its own may not provide sufficient growth advantage. The use of the YAC 954c12, which maps immediately adjacent to D13S25, defined the telomeric border of the deletion in some of the cases. Inv(14)(q11q32) and t(14;14)(q11;q32) are characteristic of T-PLL, but are also observed in premalignant T-cell clones in patients with ataxia telangiectasia. Transition to overt leukaemia may result from loss of suppressor function. Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded.
7
UI - 21445684
AU - Edelman MJ; Quam H; Mullins B
TI - Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines.
SO - Cancer Chemother Pharmacol 2001 Aug;48(2):141-4
AD - University of Maryland Greenebaum Cancer Center, Baltimore 21201-1595, USA. medelman@umm.edu
PURPOSE: To evaluate in vitro interactions of carboplatin, gemcitabine and paclitaxel in molecularly defined non-small-cell lung cancer lines. MATERIALS AND METHODS: Three NSCLC lines, A549 (p16-,p53 wt, Rb wt), Calu-1 (p16-, p53-, Rb+) and H596 (p16 wt, p53 mut, Rb-) were utilized. Cells were exposed to carboplatin, gemcitabine and paclitaxel as individual drugs and in two- and three-drug combinations with various sequences of administration. Cytotoxicity was assessed with the MTT assay. Interactions between the drugs (additive, synergistic and antagonistic) were evaluated by median effect analysis. RESULTS: Gemcitabine and carboplatin were synergistic in all three cell lines. In the A549 line, this synergy was most pronounced when gemcitabine preceded carboplatin. For three-drug combinations, paclitaxel was synergistic with gemcitabine and carboplatin regardless of sequence of administration. CONCLUSIONS: In vitro modeling of gemcitabine and carboplatin as well as gemcitabine/carboplatin and paclitaxel demonstrates synergistic interaction regardless of p16, p53, or Rb status.
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