Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraffin-embedded, formalin-fixed tissue samples from 145 cats with lymphoma were analyzed for cluster of differentiation 3 (CD3, a surface antigen) immunoreactivity, argyrophilic nucleolar organizer region (AgNOR) frequency, and proliferating cell nuclear antigen labeling index (PCNA-LI). This information along with signalment, anatomic site, and feline leukemia virus (FeLV) antigen status was used to determine the potential of these indicators to predict response to therapy, remission, and survival times, and to characterize cats with lymphoma in the era of general availability of FeLV testing and vaccination. Alimentary lymphoma, primarily occurring in older, FeLV-negative cats, was the most common site of involvement. Although the majority of tumors from FeLV-positive cats were CD3-immunoreactive, only one half of CD3-immunoreactive tumors occurred in FeLV-positive cats. Median remission duration and survival times were 126 days and 143 days, respectively, for all cats. Measures of tumor cell proliferation (AgNOR frequency and PCNA-LI) and CD3-immunoreactivity were not predictive of outcome. When all prognostic factors were accounted for by multivariate analysis, response to therapy, FeLV status, and clinical substage were predictive of outcome. FeLV-negative cats that achieved a complete response following induction therapy were likely to have durable (i.e., > 6-month) responses, particularly when doxorubicin was included in the chemotherapy protocol. However, FeLV-positive cats had significantly shorter remission and survival times with available chemotherapeutic protocols.
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PMID:Feline lymphoma (145 cases): proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats. 977 11

The WAF1/Cip1 gene product is an important regulator at the G1 checkpoint in the cell cycle. WAF1/Cip1 expression can be activated through p53-dependent and p53-independent pathways. The WAF1/Cip1 protein binds to cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. In this preliminary study, we analyzed with Western blot assays the steady-state levels of the WAF1/Cip1 protein in the leukemia cells of 100 untreated acute myelogenous leukemia (AML) patients. Normal bone marrow cells from six donors were used as a control. The results of these analyses showed that the levels of the WAF1/Cip1 protein were very low in normal marrow cells and in the leukemia cells of 83 AML patients. High levels of WAF1/Cip1 were detected in 17 patients; these patients with high WAF1/Cip1 levels were significantly less likely to achieve complete remission (41% versus 69%, P = 0.03) and were four times as likely to be resistant to therapy (47% versus 12%, P = 0.003) as patients with very low levels of WAF1/Cip1. Median survival was 38 weeks for patients having very low expression levels versus 11 weeks for patients having high expression levels (P = 0.04). The WAF1/Cip1 level was an independent predictor for response but not survival in a stepwise multivariate regression analysis. Southern blotting analyses did not detect deletion of the WAF1/Cip1 gene in the 12 negative WAF1/Cip1 AML samples tested. Also, the level of WAF1/Cip1 protein expression was not correlated with overexpression of cyclin D1, cyclin E, proliferating cell nuclear antigen, cyclin-dependent kinase 4, or p53 in the leukemia cells. However, the levels of cyclin D1, cyclin E, and cyclin-dependent kinase 4 were elevated in most of the AML samples compared with that in normal marrow. We hypothesize that high-level constitutively expressed WAF1/Cip1 in tumor cells may result in an indolent state that is refractory to chemotherapy drugs. We conclude that the WAF1/Cip1 expression level may be an important prognostic factor for response to therapy and survival in AML patients.
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PMID:High levels of constitutive WAF1/Cip1 protein are associated with chemoresistance in acute myelogenous leukemia. 981 79

The principal objectives of this study were to determine the feasibility of escalating doses of the hydrophilic topoisomerase I (topo I) inhibitor topotecan (TPT) as a 30-min infusion daily for 5 days in adults with refractory or relapsed acute leukemia and to study the pharmacokinetic behavior of high doses of TPT and pharmacodynamic determinants of TPT activity. Fourteen patients received 27 courses of TPT at doses ranging from 3.5 to 5.75 mg/m2/day every 3 weeks. A constellation of unusual adverse effects, consisting of high fever, rigors, precipitous anemia, and hyperbilirubinemia, was the principal dose-limiting toxicity of high doses of TPT on this schedule. These toxicities were consistently intolerable at the 5.75 mg/m2/day dose level; however, they were neither severe nor common at lower doses. Although the precise etiology of these effects is not known, high doses of TPT may induce acute hemolytic reactions in this patient population. Severe, albeit transient, mucositis was experienced by two of eight patients in 2 of 17 courses at the next lower dose level, 4.5 mg/m2/day, which was determined to be the maximum tolerated dose and the dose recommended for further trials. The pharmacokinetic behavior of TPT at high doses was not dose dependent and resembled that at lower doses. In view of preclinical data suggesting that TPT sensitivity might correlate with topo I levels, topo I content in leukemia blasts was assessed by Western blotting. Variations in topo I content were observed. Moreover, strong correlations were evident between topo I content and two markers of proliferation, proliferating cell nuclear antigen and nuclear protein B23, raising the possibility that differences in topo I content observed among various leukemia specimens might reflect differences in the proliferating fractions of cells in various leukemia samples. Although complete clearance of circulating leukemia blasts occurred in most courses, neither sustained responses nor hematopoietic recovery were observed in the heavily pretreated, poor-risk patients enrolled in this study, and it was not possible to correlate these differences in topo I content with clinical response. These results indicate that substantial dose escalation of TPT as a 30-minute infusion for a 5-day schedule above myelosuppressive doses is feasible in adults with refractory or relapsed leukemias; however, further development of alternate high-dose schedules in leukemia may be warranted in view of the nature of the dose-limiting toxicity and the lack of sustained clinical responses in this preliminary investigation.
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PMID:A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia. 981 50

Nuclear matrices were prepared from isolated subtypes of human hematopoietic cells and from cultured leukemia cells. The nuclear matrix proteins were analyzed by high-resolution two-dimensional gel electrophoresis and computer-assisted image analysis. While more than 200 protein spots were shared among the cells, about 50 distinct spots were found characteristic for individual cells or groups of related cells. This allowed to differentiate between hematopoietic cells and nonhematopoietic cells, lymphocytes and myeloid cells, monocytes, neutrophils, and promyelocytic leukemia cells. B and T lymphocytes could not be differentiated. Myeloid cells with their polymorph nuclei were characterized by the presence of 13 and by the absence of seven distinct spots, as well as by low concentrations of nuclear lamins and of heterogeneous nuclear ribonucleoproteins. Neutrophils with multilobular nuclei displayed six additional spots, while lacking 18 nuclear matrix protein spots. The nuclear matrix of proliferating cells showed three distinct spots in addition to proliferating cell nuclear antigen, increased concentrations of numatrin (B23), and heterogeneous nuclear ribonucleoproteins. The described cell-specific nuclear matrix proteins may represent new markers for hematopoietic cells.
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PMID:Nuclear matrix proteins specific for subtypes of human hematopoietic cells. 1002 7

The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a transcriptional transactivator and viral oncogene. Since cellular transformation has been frequently linked to alterations in genome stability, we investigated the effect of Tax on nucleotide excision repair (NER), a prominent cellular DNA repair pathway. Cells expressing Tax exhibited a reduced capacity for NER as measured by unscheduled DNA synthesis and host cell reactivation assays. The cellular proliferating cell nuclear antigen (PCNA) gene product regulates DNA replication and repair pathways, including NER. Since Tax activates transcription of the PCNA promoter, we investigated whether this activity contributes to the reduction of NER. Tax increased endogenous PCNA protein expression, and analysis of Tax mutant proteins demonstrated that the reduction in NER correlated with Tax transactivation of PCNA gene expression. Direct overexpression of PCNA also reduced NER. We propose that overexpression of PCNA, and disruption of NER induced by Tax, predisposes cells to accumulate DNA damage and contributes to HTLV-1 transformation.
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PMID:Disruption of nucleotide excision repair by the human T-cell leukemia virus type 1 Tax protein. 1019 28

Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) was performed in skin from patients with various malignant and nonmalignant skin diseases using anti-PCNA monoclonal antibodies. The malignant diseases included squamous cell carcinoma (SCC), adult T lymphotrophic leukemia (ATL), mycosis fungoides, malignant melanoma and malignant lymphoma, and the nonmalignant diseases included severe treatment-resistant atopic dermatitis (AD), psoriasis vulgaris, verruca vulgaris, and others. The percentage of PCNA-positive cells (the labeling index, LI) was highest for the malignant diseases (56.5+/-7.1%). The LIs for severe treatment-resistant AD, psoriasis, and verruca vulgaris were also significantly higher than those for the normal control or nonlesional skin of the patients. The PCNA LIs were, however, not significantly elevated in eczema and contact dermatitis. The high PCNA LIs in severe AD and psoriasis vulgaris were considerably lower in the skin improved by treatment. Labeling with Ki67, a nuclear protein expressed in cycling cells, was also performed in skin from subsets of each patient group. The results were very similar to those found with PCNA labeling. PCNA-positive cells were found throughout the dermis as well as the basal layer in the malignant diseases, whereas they were found only in the basal layer in the nonmalignant diseases. The results suggest that in human skin diseases, the extent of staining for PCNA, which is a cofactor of DNA polymerase-delta and is essential for cell proliferation, correlates with the extent to which the disease is treatment-resistant. In addition, our findings suggest that the PCNA LI and distribution of PCNA-positive cells in the skin may be helpful in the early diagnosis of skin malignancies.
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PMID:Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases. 1048 11

Selaginella tamariscina, an oriental medicinal plant, was extracted using water and several organic solvents, and each fraction was assayed for its tumoricidal effects with 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT). Influences on expression of p53 tumor suppressor gene and induction of G1 arrest in the cell cycle were analyzed by Northern blotting and flow cytometry, respectively. The modifying effects of pulverized Selaginella tamariscina on cell turnover in the stomach were also investigated in rats given 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gavage and then fed a diet containing 5, 1 or 0% Selaginella tamariscina. Fractions I-V showed significant tumoricidal effects against cultured human leukemia cells whereas these fractions did not affect normal human lymphocytes. Among the effective fractions, the water-extracted fraction (V) efficiently increased p53 gene expression and induced G1 arrest. The 1% Selaginella tamariscina feeding caused a significant reduction (P < 0.05) in the proliferating cell nuclear antigen-(PCNA) labeling index of the glandular stomach epithelium as compared with the MNNG-alone group value although 5% Selaginella tamariscina feeding was only associated with a tendency for decrease. These results suggest that Selaginella tamariscina could be a candidate chemopreventive agent against gastric cancer.
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PMID:Effects of Selaginella tamariscina on in vitro tumor cell growth, p53 expression, G1 arrest and in vivo gastric cell proliferation. 1050 82

Mantle cell lymphoma (MCL) is a tumor of intermediate-size, IgM+, IgD+ B cells derived from the mantle zone of the germinal center. Little is known about its specific immunologic features or responsiveness to T cell-derived signals. In this work, we evaluated the proliferation and cell cycle properties of freshly isolated MCL cells after CD40 ligation, in the absence and presence of interleukin 4 (IL-4). In each MCL case examined, there was a marked growth-enhancing effect of these two stimuli characterized by improved viability, augmented expression of Ki-67, and induction of the proliferating cell nuclear antigen (PCNA). Cyclin D1 was expressed throughout the cell cycle in MCL cells induced to enter S phase. From these investigations, we conclude that the biology of MCL B lymphocytes is affected by CD154 (CD40 ligand) and IL-4, two signals usually provided by CD4+ T cells. The capacity to manipulate the activation and cell cycle state of MCL cells by these specific immunological stimuli may be exploited to confer susceptibility to chemotherapy agents and develop novel therapies in this disease.
Leukemia 2000 Feb
PMID:Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4. 1067 47

Checkpoint alterations that impact cell cycle and apoptosis responses to therapeutic treatments may produce drug resistance in acute myeloid leukemia (AML). To study these, we have developed flow cytometry assays of checkpoint function that also allow quantitation of key molecular regulators of apoptosis and cell cycle. We have used three-color (3C) assays, with FITC-labeled anti-BCL-2 and PE-labeled anti-proliferating cell nuclear antigen (PCNA) antibodies, and the DNA dye 7-aminoactinomycin, to characterize primary leukemia cells identified in DNA x side light scatter (SSC) histograms. We showed that 3C assays are accurate and reproducible in analyses of leukemia cell lines and of primary AML and normal bone marrow samples (Banker et al.: Blood 89: 243-255, 1997; Banker et al.: Leukemia Res 22: 221-239, 1998; Banker et al.: Clin Cancer Res 4: 3051-3062, 1998). To further confirm the validity of our SSC leukemia cell gating and to address whether immunophenotypic AML subsets might have different biologic properties, we have now designed four-color (4C) flow assays to characterize checkpoint status in leukemic blasts specifically identified by surface immunostaining. In modeling this assay strategy, PE/Cy5-labeled anti-CD34 antibody was used to detect blasts, with FITC-labeled anti-BCL-2, PE-labeled anti-PCNA antibodies, and Hoechst 33342 (H33342) DNA dye. Four-color CD34-gated data was concordant with 3C, SSC-gated data for leukemia cell lines and for most primary AML samples with high and intermediate blast counts. BCL-2 and PCNA immunopositivity and sub-G1 apoptosis determinations were different in the CD34-gated versus SSC-gated blasts in particular samples with smaller CD34(+) subsets, suggesting that leukemia samples can contain blast subsets with different biologic properties. On the other hand, PCNA-gated cell-cycle distributions in untreated cells and G1 versus S phase cell-cycle arrests after cytosine arabinoside treatments were completely concordant in 4C and 3C assays. We conclude that both 3C and 4C assays can be used to characterize protein expression and cell-cycle drug response patterns in leukemia blasts, but that 4C assays may additionally allow discrimination of these properties in immunophenotypic leukemia subsets.
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PMID:Three-color versus four-color multiparameter cell cycle analyses of primary acute myeloid leukemia samples. 1079 45

Malignant neoplasms represent one-third of all pediatric salivary gland tumors. Mucoepidermoid carcinoma (MEC) composes 51% of malignant tumors and 16% of all salivary gland neoplasms in pediatrics. Prognostic factors in MEC in pediatric patients have not been well defined. Histopathologic features, clinical outcomes and proliferation markers in 26 pediatric patients (median age 11 years; 19F:7M) with salivary gland MECs were evaluated retrospectively. MEC histocytologic grading used a three-tiered system. Proliferation was assessed by determining the percentage of tumor cells immunoreactive for PCNA and Ki-67. Tumor site was 16 parotid, eight submandibular, one base of tongue and one maxillary lip. Median tumor size was 2.5 cm (range 1.5-5 cm). MEC grade was nine low grade (LG), 15 intermediate grade (IG) and two high grade (HG). Metastatic disease and capsular invasion occurred in five cases, while perineural invasion was noted in three cases. Mean percentage of tumor cells immunoreactive for proliferation markers is as follows: PCNA: LG 9%, IG 17%, HG 32%; and Ki-67: LG 7%, IG 12%, HG 26%. Treatment was surgical in 21 cases, and surgery with chemotherapy and radiotherapy in five cases. Two patients with high grade MECs died of disease (21, 44 months). Twenty-four patients had no evidence of disease at a median follow-up of 104 months (range 30-298 months). MECs were second malignancies in two children with prior radiotherapy and chemotherapy for leukemia and histiocytosis. Low and intermediate grade salivary gland MECS in a pediatric population may have a favorable outcome when compared with high grade MECs. Proliferation markers appear to be linked to histocytologic MEC grade and may provide information regarding biologic behavior of salivary gland MECs in children and adolescents.
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PMID:Mucoepidermoid carcinoma of salivary glands in children and adolescents: assessment of proliferation markers. 1096 53


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