Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 +/- 0.8 vs. 2.8 +/- 1.5, P < 0.01). beta-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.
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PMID:Dietary sodium gluconate protects rats from large bowel cancer by stimulating butyrate production. 1505 51

A preliminary clinical experience suggested tazarotene, a new acetylenic retinoid, as an effective alternative topical treatment of basal cell carcinomas (BCC). The mechanisms of action of this synthetic retinoid, however, have not been yet clarified. In this work we assessed the in vivo effects of daily application of tazarotene for 24 wk, on 30 small superficial and nodular BCC, and the in vitro effects of tazarotene on immortalized basal and squamous tumor epidermal cells. Cellular proliferation, apoptosis and changes in expression of retinol and retinoic acid receptors (RAR), p53, bcl-2, and bax were studied by immunohistochemistry, western blotting and PCR. Overall, 76.7% of treated tumors showed >50% regression. Complete healing was observed in 46.7% of all treated BCC, without recurrences at 2-y observation. Regression was associated with reduced proliferation and increased apoptosis, demonstrated by Ki-67- and TdT-mediated dUTP-biotin nick-end labelling-positive nuclear staining, and with enhanced RAR-beta and bax expression, with RAR-alpha and -gamma expression unchanged. In vitro, tazarotene induced a concentration-dependent increase of RAR-beta and bax associated with a greater rate of apoptosis and growth inhibition in basaloid tumor cells compared with squamous tumor cells. Our studies provide convincing evidence that tazarotene induces BCC regression possibly by synergistic RAR-beta-dependent anti-proliferative and pro-apoptotic pathways.
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PMID:Evidence of increased apoptosis and reduced proliferation in basal cell carcinomas treated with tazarotene. 1510 95

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for > or =4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
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PMID:Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. 1516 42

Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.
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PMID:In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. 1519 29

Eicosapentaenoic acid (EPA) has been demonstrated to induce apoptosis and cell cycle arrest in various cancer cell lines in vitro. In this study, we investigated the anti-tumor effects of EPA on hepatoma cell lines and the mechanisms responsible for induced cell death. Three hepatoma cell lines tested had different p53 status: HepG2 with a wild-type p53; Hep3B, of which the endogenous p53 was deleted; and Huh7 with its p53 mutated. MTT assay showed reduced viability of HepG2 cells after exposure to EPA, and the cytotoxicity of EPA was time and dose dependent. However, EPA had no effect on the viability and cell death in the two other hepatoma cell lines containing dysfunctional p53. DNA fragmentation analysis and TUNEL (terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine diphosphate [dUTP] nick end labeling) staining showed a typical pattern of DNA laddering and DNA breaks staining, respectively, in wild-type p53-containing HepG2 cells after EPA treatment. We also observed that EPA induced transient nuclear accumulation of P53 protein that subsequently up-regulated the expression of Fas messenger RNA and protein in HepG2 cells. In contrast, these findings were not observed in Hep3B and Huh7 cells exposed to EPA. Most notably, EPA-induced apoptosis in HepG2 cells could be reduced almost completely by treatment with FasL antisense oligonucleotides. We conclude that EPA inhibits the growth of HepG2 cells and mediates its effect, at least in part, via the Fas-mediated apoptosis. It appears that the effects of EPA on hepatoma cells are determined by the status of p53 and that wild-type p53 is a prerequisite for the anticancer effect of EPA.
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PMID:Eicosapentaenoic acid induces Fas-mediated apoptosis through a p53-dependent pathway in hepatoma cells. 1528 29

In the literature, sufficient attention has not been paid to the precise subcellular localization of immunohistochemical signals, the knowledge of which is essential for proper interpretation of immunostains and distinction of genuine staining from biotin-associated or other nonspecific stainings. The subcellular localization of the signals can in fact be easily deduced from the known biologic or ultrastructural characteristics of the antigens. Extracellular antigens obviously are located in the extracellular compartment. Cellular antigens fall into 3 major groups: membranous, nuclear, and cytoplasmic. Membranous antigens include cell adhesion molecules (such as E-cadherin, N-CAM), cell surface/transmembrane receptors and proteins (such as tyrosine kinase receptors, most leukocyte antigens, CD10, CEA), and molecules linking surface molecules to cytoskeleton (such as beta-catenin, dystrophin). Nuclear antigens include cell cycle-associated proteins (such as cyclins, p16, Ki-67), nuclear enzymes (such as TdT), transcription factors (such as TTF-1, CDX-2, myogenin, PAX-5), tumor suppressor gene products (such as p53, p63, WT1, Rb), steroid hormone receptors (such as ER, PR), calcium-binding proteins (such as S-100 protein, calretinin), and some viral proteins (such as CMV, herpes). Cytoplasmic antigens can take up a granular pattern due to localization in organelles, granules, or secretory vesicles (such as chromogranin, hormones, lysozyme, HMB-45), fibrillary pattern attributable to the filamentous nature of the molecules (intermediate filaments and microfilaments), or diffuse or patchy pattern due to localization in the cytosol or large vesicles (such as myoglobin, albumin, thyroglobulin). Aberrant localization of the molecules, when present, can provide important insight into disease processes and aid in their diagnosis, such as loss of membranous E-cadherin expression in lobular breast carcinoma, aberrant nuclear localization of beta-catenin in colorectal adenocarcinoma, pattern of ALK staining in anaplastic large cell lymphoma correlating with the different types of chromosomal translocations, presence of additional cytoplasmic CD10 staining in the enterocytes indicative of microvillous inclusion disease, and "reversed" staining for EMA in micropapillary mammary carcinoma.
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PMID:Subcellular localization of immunohistochemical signals: knowledge of the ultrastructural or biologic features of the antigens helps predict the signal localization and proper interpretation of immunostains. 1530 32

Early plasmacytoid dendritic cell (pDC) leukemia/lymphoma has recently been described as a CD4(+)CD56(+) lineage negative malignancy with characteristic clinical, morphologic, immunophenotypic, and biological features. We present a case of a 72-year-old man who was diagnosed with isolated skin involvement 30 months ago and received numerous chemotherapy cycles that did not prevent three relapses of the disease, the last two involving the bone marrow. The bone marrow was nearly completely infiltrated with small- to medium-sized blasts displaying a high nuclear to cytoplasmic ratio, a cytoplasm with faint basophilia lacking granulations or Auer rods. Small vacuoles surrounding the nucleus were frequently observed. Flow cytometry showed CD4(+), CD56(+), CD45(+), CD38(+), HLA-DR(+), CD33(+), CD123(+), CD2(-), cyCD3(-), CD7(-), CD10(-), CD11b(-), CD13(-), CD14(-), CD16(-), CD19(-), cyCD22(-), CD24(-), CD34(-), CD57(-), CD61(-), CD64(-), CD65(-), cyCD79a(-), CD117(-), MPO(-), and TdT(-) population. At the second bone marrow relapse, CD117 was also positive. Our patient was initially treated with acute myeloid leukemia-type chemotherapy, later he was given acute lymphoblastic leukemia-type treatment, and at the last relapse he received CHOP chemotherapy. Each treatment led to rapid response of tumor manifestations with disease-free intervals of 7 months, 9 months, and 8 months, respectively. Although patients usually have an ominous prognosis, with only 25% living more than 24 months, our patient is alive after 30+ months and has again achieved complete remission after the last chemotherapy.
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PMID:Early plasmacytoid dendritic cell leukemia/lymphoma coexpressing myeloid antigenes. 1531 55

Non-small cell lung cancer (NSCLC) includes a group of tumors that respond poorly to drugs. cis-Diamminedichloroplatinum(II) (cis-DDP) toxicity still remains problematic, and not completely solved by the improvement of supportive care. Therefore, the cis-Pt(II) complex of 3-aminoflavone was selected from cis-DDP analogues with a more favourable toxic profile towards normal cells and at least similar or better anti-tumor activity in comparison with cis-DDP. The aim of this research is to compare the ability of the cis-Pt(II) complex of 3-aminoflavone and cis-DDP to induce apoptosis and necrosis in the human non-small cancer cell line A549. Trypan blue dye exclusion, fluorochrome staining (acridine orange/ethidium bromide double staining), MTT and TUNEL (TdT-mediated dUTP Nick-End Labeling) assays were used. The results obtained show that the cis-Pt(II) complex of 3-aminoflavone is more active in inducing apoptosis and necrosis and in decreasing viability in A549 cells than cis-DDP, which suggests that it could be a potential chemotherapeutic drug.
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PMID:Induction of apoptosis and necrosis in A549 cells by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. 1532 49

Biphenotypic acute leukemias (BALs) are uncommon. Most are of myeloid-B-cell or myeloid-T-cell lineage. We report herein a 70-year-old man with an unusual acute leukemia where the blasts expressed both B- and T-lymphoid markers. He presented to us with an enlarging cutaneous tumor. The presenting peripheral blood and bone marrow aspirate showed 40% and 90% blasts, respectively, which were negative for the usual cytochemical stains. The flow cytometric analysis revealed that the blasts were positive for CD19, CD20, CD22, cytoplasmic (Cyt) CD79a, CD10, Cyt CD3, CD5, CD7, CD4, HLA-DR, TdT, and were negative for myeloid markers. According to the scoring system from the European Group for the Immunological Characterization of Acute Leukaemias (EGIL), this case was an unequivocal B-cell/T-cell BAL. Conventional cytogenetic analysis revealed 46XY [t(4;11)(q31;q13), add(8)(q24), der(9)del(9)(p21)del(9)(q32q34), -13, +mar] in all 25 metaphases analyzed. Fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) for 11q23 rearrangements as well as t(9;22) were negative. PCR for both TCR-gamma and IgH gene analyses revealed polyclonal rearrangements. We postulate that this case of BAL might have arisen from the putative common lymphoid progenitor cell.
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PMID:Acute lymphoblastic leukemia with the phenotype of a putative B-cell/T-cell bipotential precursor. 1538 7

Drugs that inhibit the function of heat shock protein 90 (Hsp90) are of interest in the treatment of pediatric cancers because these agents deplete the cellular levels of signaling molecules that are important for the growth and survival of many childhood tumors. To generate preclinical data in anticipation of clinical trials of Hsp90 inhibitors in children, we evaluated the effects of the Hsp90 inhibitor geldanamycin (GA) alone and in combination with cis-platinum (II)-diamine dichloride (cisplatin) in pediatric tumor cells. Immunoblotting demonstrated depletion of the Hsp90 client proteins AKT and the type 1 insulin-like growth factor receptor (IGF1R) in a panel of pediatric tumor cell lines after exposure to GA. Drug exposure also led to a dramatic decrease in cell survival/proliferation in MYCN-amplified and non-amplified neuroblastoma cells. Moderate inhibition of survival/proliferation was observed in RB-deficient and wild-type osteosarcoma cells. Treatment of neuroblastoma and osteosarcoma cell lines with GA in combination with cisplatin resulted in greater than additive inhibition of survival/proliferation based on median dose analysis. Exposure to this drug combination also resulted in a marked increase in nuclear fragmentation as assessed by terminal deoxynucleotide transferase-mediated UTP nick end labeling (TUNEL) analysis. Combined exposure also abrogated the ability of GA to induce a cytoprotective heat shock response and resulted in Hsp90 adduct formation. Our findings suggest that Hsp90 inhibitors may prove useful either alone or as a component of multi-drug regimens in the treatment of neuroblastoma and osteosarcoma.
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PMID:Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin. 1545 81


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