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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour cell nuclei display achromasia in smears relative to methylene blue and to other low-affinitive ionic dyes. In the course of the smear air-drying the tumour DNA undergoes conformational changes as evidenced by enhanced ethidium and monomer acridine orange uptake and increased sensitivity to DNAse I hydrolysis. Very mild treatment with bleomycin prevents nuclear achromasia with methylene blue in tumour cells. It is concluded that the phenomenon of nuclear achromasia of tumour cells is due to the properties of secondary structure of their DNA.
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PMID:[Conformational changes in the chromatin of tumor cells and the phenomenon of nuclear achromasia]. 245 24

The synthesis of two depsipeptides including a peptide metal-chelating moiety (Gly-His-Lys) and a moiety with DNA affinity, namely either glycyl-anilino-9-aminoacridine 1 or 2'-(2-aminoethyl)-4-methoxycarbonyl-2",4'-bithiazole 2, has been carried out. The goal was to introduce separately on the same molecule the two factors contributing to the biological activity of many anti-tumor drugs. The interaction of both drugs with DNA has been studied and the acridine ring of 1 was found to intercalate in the double helix. The production of free radicals has been evidenced by spin-trapping for 1 although both compounds were revealed to be good copper-chelating agents. In vitro cytostatic activity and inhibition of [3H]-thymidine incorporation were obtained for 1 while 2 exhibited no activity in both tests. In view of these results, it can be pointed out that the anti-tumor properties of such drugs rely (1) on their ability to reach and to bind DNA and (2) on redox mechanisms involving interactions between the drugs, metals and molecular oxygen. The latter phenomenon leads to the formation of active radical species, able to degrade the DNA.
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PMID:Synthesis, biological activity and DNA interaction of anilinoacridine and bithiazole peptide derivatives related to the anti-tumor drugs m-AMSA and bleomycin. 247 98

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.
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PMID:Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge. 254 17

The purpose of this study was to examine radiation-induced DNA strand breakage and repair in quiescent and proliferating human tumor cells in vitro and determine their relationship to radiation sensitivity and potentially lethal damage repair (PLDR). Using centrifugal elutriation we have isolated from fed plateau-phase cultures of HEp-3 human squamous carcinoma cells, relatively pure populations of quiescent and proliferating cells. This was confirmed by both [3H]-thymidine labelling and acridine orange (AO) staining with flow cytometry. Quiescent cells were more sensitive to ionizing radiation (Do = 0.97 Gy) than were proliferating cells (Do = 1.28 Gy). However, quiescent cells showed higher repair of potentially lethal damage (PLDR) than did proliferating cells. Repair of single-strand breaks (ssb) and double-strand breaks (dsb) as measured by filter elution did not differ significantly between quiescent and proliferating cells. For both populations, ssb and dsb repair kinetics and final damage remaining were the same, suggesting that repair of DNA strand breaks is not entirely responsible for the difference in radiation sensitivity between quiescent and proliferating cells.
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PMID:Radiation-induced DNA damage and repair in quiescent and proliferating human tumor cells in vitro. 256 35

Bivariate flow cytometry (FCM) was used to study immunofluorescent T16 mouse monoclonal antibody (Mab) binding simultaneously with propidium iodide DNA measurements in bladder irrigation specimens from 30 patients with a history of bladder cancer. Aliquots of the same samples were stained with acridine orange (AO) and examined by conventional FCM. T16 Mab is believed to be specific for epithelial cells in this type of specimen and stained from 13% of the cells in a patient with cystitis to 95% of the cells in a patient with an atypical papilloma. In combination with DNA measurements, this antibody increased the sensitivity of FCM in patients with severe cystitis and relatively small numbers of tumor cells, but the diagnostic specificity may be decreased and the criteria established for interpreting univariate flow cytometry may have to be re-evaluated and modified.
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PMID:Initial evaluation of a new epithelial antigen (T16) for bivariate flow cytometry of bladder irrigation specimens. 271 17

DNA content and in situ sensitivity to denaturation were analyzed by flow cytometry of individual cell nuclei isolated from 40 breast carcinomas, nine fibroadenomas, and 14 samples of normal breast tissue. The extent of DNA denaturation induced by acid was expressed as alpha t, which represents the fraction of DNA staining metachromatically red with the fluorochrome acridine orange. In all cases of normal breast tissue DNA was very sensitive to denaturation and the frequency distribution of alpha t values was unimodal with over 90% of cells having alpha t above 0.6. All fibroadenomas were diploid; four had unimodal alpha t as in normal tissue and five had a bimodal distribution with an additional peak below 0.6. Twenty-seven adenocarcinomas (67%) had a DNA index above 1.0; of these 24 had bimodal alpha t distributions. Among 13 diploid carcinomas 10 had bimodal alpha t distributions. Statistically significant differences were observed in alpha t distributions of normal versus tumor breast tissue (P less than 0.005). In normal tissue and in all tumors a predominant proportion of cells with S and G2 + M DNA content were characterized by DNA resistant to denaturation (alpha t below 0.6). Of interest, the diploid cells from aneuploid tumors which may represent reactive host cells often displayed bimodal distributions of alpha t. These results may be interpreted in light of earlier studies demonstrating increased resistance of DNA to denaturation in diffuse chromatin of proliferating and/or transcriptionally active cells, and greater sensitivity to denaturation of DNA in condensed chromatin of quiescent cells. Thus, the presence of the second peaks representing cells with low alpha t values in breast tumors may indicate a high proportion of proliferating cells, whereas high alpha t populations may represent quiescent and differentiating (condensed chromatin) or dying (pycnotic nuclei) cells. It is likely that the low alpha t diploid cells detected in aneuploid tumors may represent the reactive (transcriptionally active and/or proliferating) infiltrating host cells (i.e., lymphocytes, monocytes) whose presence may also be of prognostic value. The data suggest that a DNA denaturability assay may be useful to characterize tumor and infiltrating host cell populations.
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PMID:DNA in situ sensitivity to denaturation as a marker of human breast tumors. 280 80

To determine whether a low pH intracellular "sorting" step is required to route peptides into secretory granules, the effects of pH altering drugs on the biosynthesis and secretion of peptides by AtT-20 mouse corticotrope tumor cells and rat intermediate pituitary cells were examined. Doses of each drug maintaining normal protein synthesis and cell morphology, while obliterating the intracellular pH gradients detected by acridine orange fluorescence, were experimentally determined. Regions of the cell rich in secretory granules were localized by immunocytochemistry and were found to coincide with organelles with a low internal pH. Biosynthetic labeling experiments were coupled with immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel analyses to examine the biosynthesis and secretion of corticotropin (ACTH(1-39], alpha-melanotropin, ACTH(18-39), beta-endorphin, gamma-melanotropin, alpha-amidated joining peptide, and the NH2-terminal region of pro-ACTH/endorphin. Chloroquine (20-40 microM) and a mixture of NH4Cl and methylamine (2-5 mM each) dissipated pH gradients but had no effect on the synthetic rate of pro-ACTH/endorphin, the extent and rate of precursor processing to smaller peptides, the rate of basal secretion of the various peptides, or the extent to which secretion of each of the peptides could be stimulated by secretagogues. Monensin (0.1-1 microM) had no discernible effect on intracellular pH gradients yet totally blocked proteolytic processing of pro-ACTH/endorphin. Thus, a monensin-blockable step occurs in peptide processing, presumably in the trans Golgi region; however, a low pH chloroquine-sensitive sorting step is not required for processing or for routing peptides to a stable storage form which can be released in response to secretagogues.
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PMID:The role of a low pH intracellular compartment in the processing, storage, and secretion of ACTH and endorphin. 283

The purpose of this study was to examine the distribution pattern of acridine orange (AO) binding to DNA in transformed cells and derived tumor cells. Two cell clones from hamster embryonic fibroblasts (HEF) transformed by herpes simplex virus type 2, tumor cells derived from the transformed cell clones, and normal HEF in culture were processed for ultracytochemistry. Uptake studies and autoradiography using [3H] thymidine and [3H]-uridine were also performed. Ultrastructural examination revealed that AO became bound to DNA exclusively within the euchromatin portion of the cell nucleus. The percentages of AO-positive cell nuclei were 18.0% and 15.5% in transformed cell clones and 21.3% and 18.3% in the derived tumor cells, but only 2. 7% in the HEF. The average amounts of AO-chromatin interaction products increased in the transformed and tumor cells. Labeling indices of [3H] thymidine were 28.9% and 33.2% in both the transformed cell clones, 32.4% and 36.9% in their tumor cells, and 3.7% in the HEF. Euchromatin/heterochromatin (EU/HEF) ratios were found to be higher in AO-positive nuclei than in AO-negative nuclei in each cell line. The increase in the number of AO-positive nuclei and in the EU/HET ratios may represent a basic reaction of cell nuclei in transformation and tumorigenesis.
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PMID:Electron microscopic localization of acridine orange chromatin interaction products in cells transformed by herpes simplex virus type 2. 285 Dec 56

The nitroacridine derivative 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) is selectively cytotoxic to hypoxic tumor cells in culture. However, the compound undergoes reductive metabolism too rapidly, with the reduction not being sufficiently inhibited by molecular oxygen in aerobic tissues, for it to demonstrate the same activity in vivo. In a search for derivatives with lower reduction potentials, we have synthesized and evaluated a series of derivatives bearing 4-substituents with a wide range of electronic properties. The one-electron reduction potentials (E(1] of these compounds, when compared under conditions of equivalent ionization, were highly correlated with sigma p values. However, at pH 7 the influence of substituent electronic properties was modified by prototrophic equilibria, with the basic nature of the acridine limiting the extent to which ring substituent electronic effects can be used to modulate reduction potential of the 1-nitro group. Nevertheless, comparison of the kinetics of the killing of AA8 cells under hypoxia suggests that some metabolic stabilization of the compounds can be achieved by the use of electron-donating substituents, with such compounds retaining the hypoxia-selective toxicity of nitracrine in cell culture. However, the 4-substituted nitracrines show no clear relationship between E(1) and cytotoxic potency, in distinct contrast to simpler nitroheterocycles such as nitroimidazoles.
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PMID:Hypoxia-selective antitumor agents. 1. Relationships between structure, redox properties and hypoxia-selective cytotoxicity for 4-substituted derivatives of nitracrine. 290 36

We have used biologically active derivatives of beta-nerve growth factor (NGF), modified by biotinylation via carboxyl groups, to target the specific binding of liposomes to cultured rat and human tumor cells bearing NGF receptors. Liposomes, to be used for targeting, were prepared by conjugating streptavidin to phospholipid amino groups on liposomes prepared by reverse-phase evaporation. Approximately 2,000 streptavidin molecules were incorporated per liposome. Addition of biotinylated NGF, but not of unmodified NGF, could mediate the subsequent binding of radiolabeled streptavidin-liposomes to rat pheochromocytoma PC12 cells in suspension at 4 degrees C. In contrast, incubation with biotinylated NGF did not mediate the binding of hemoglobin-conjugated liposomes. Under optimal incubation conditions, approximately 570 streptavidin-liposomes were specifically bound per cell. Biotinylated NGF was also used to obtain specific binding of streptavidin-liposomes containing encapsulated fluorescein isothiocyanate-labeled dextran to PC12 cells or human melanoma HS294 cells. When HS294 cells were incubated at 37 degrees C following targeted liposome binding at 4 degrees C, the cell-associated fluorescence appeared to become internalized, displaying a perinuclear pattern of fluorescence similar to that observed when lysosomes were stained with acridine orange. Trypsin treatment abolished cell-associated fluorescence when cells were held at 4 degrees C but did not alter the fluorescence pattern in cells following incubation at 37 degrees C. When liposomes containing carboxyfluorescein, a dye capable of diffusing out of acidic compartments, were targeted to HS294 cells, subsequent incubation at 37 degrees C resulted in diffuse cytoplasmic fluorescence, suggesting that internalized liposomes encounter lysosomal or prelysosomal organelles.
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PMID:Targeting of liposomes to cells bearing nerve growth factor receptors mediated by biotinylated nerve growth factor. 302 60


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