A new type of ionizing radiation-induced DNA base damage, 8-hydroxyguanine formation, was found in DNA that had been irradiated by X-rays in aqueous solution. The extent of this modification linearly increased with increase in the X-ray dose up to 40 krad. When an OH radical scavenger, ethanol, was added to the DNA solution, the hydroxylation was inhibited almost completely, suggesting that the reaction proceeds via the formation of OH radicals.
Ataxia-telangiectasia (AT) cells are hypersensitive to the lethal effect of γ-rays, whereas little or no γ-ray induced mutation has been observed. In this work, exposure to γ-rays of an Epstein-Barr virus-transformed AT lymphoblastoid cell line, GM2783, resulted in a clear dose-dependent increase of mutation for 6-thioguanine resistance.
Adult T-cell leukemia virus associated antigen (ATLA) was detected in peripheral mononuclear cells from 29 of 35 anti-ATLA-positive mothers, but was not detected in cells from any of the neonates. Cells from breast milk of all of 12 anti-ATLA-positive mothers and semen from one of three anti-ATLA positive men were ATLA-positive.
Diethylstilbestrol, a unique carcinogen lacking measurable mutagenic potency in Salmonella, was shown to be an inhibitor of microtubule assembly in vitro using microtubule proteins isolated from porcine brains. The effective concentration of diethylstilbestrol was 10-200μM, as determined by viscometry, turbidity measurement, and electron microscopic analysis.
It was found that three synthetic anthracycline analogs lacking not only antitumor activity but also calcium-antagonizing action possessed an activity to potentiate vincristine cytotoxicity against vincristine-resistant P388 leukemia. ID-8279, one of these analogs, significantly reversed resistance to vincristine and daunorubicin by increasing their intracellular accumulation.
The effect of sodium chloride on the promotion stage of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied in male inbred Wistar rats. Rats in group I were given MNNG at a concentration of 50μg/ml in their drinking water for 12 weeks and then 1ml of saturated NaCl solution intragastrically once a week until experimental week 65. Rats in group II were given MNNG for 12 weeks and then 1ml of distilled water intragastrically once a week until week 65. Rats in group III were not treated for the first 12 weeks and were then given 1ml of saturated NaCl solution intragastrically once a week until week 65. The incidence of adenomatous hyperplasias in the glandular stomach was significantly higher in group I than in group II, but the incidences of gastric adenocarcinomas and adenomas in groups I and II were not significantly different. No neoplastic or preneoplastic changes were observed in the stomach in group III.
The effect of caffeine on the development of hepatic tumors induced by 2-acetyl-aminofluorene (2-AAF) was studied in 6-week-old male ACI rats. Rats in group 1 were fed a diet containing 0.02% 2-AAF for 18 weeks and then basal diet for 15 weeks with normal drinking water throughout. Animals in group 2 received a diet containing 0.02% 2-AAF and a solution of 0.2% caffeine as their drinking water for 18 weeks, followed by basal diet and caffeine-free water. Rats in group 3 received drinking water containing 0.2% caffeine for 18 weeks. Rats in group 4 were given a basal diet and water freely and served as controls. The experiment was terminated after 33 weeks. Both the multiplicity, i.e. the number of tumors per rat, and the size of tumors were less (P<0.001 in the former case, by Student's t-test) in group 2 than in group 1. Thus, the induction of tumors of the liver by 2-AAF was suppressed by the administration of caffeine.
The effect of cupric acetate on dimethylnitrosamine (DMN)-induced hepatocarcinogenesis in rats was investigated. The surviving rats in the group given DMN (25ppm) in the drinking water alone were killed at 26 weeks and it was found that 12 of 16 rats had developed liver tumors. In the group given DMN and cupric acetate (sc injections of 2mg of Cu/kg of body weight once a week for 26 weeks), 7 of 22 rats developed liver tumors. The incidence of liver tumors in rats given DMN and cupric acetate was thus only about 40% of that in rats given DMN alone. No tumor was observed in the group given saline or cupric acetate alone. The thymidine incorporation into the liver DNA of rats was measured at 2 and 4 weeks after the start of the carcinogenicity experiment. The thymidine incorporation into the liver DNA of rats given DMN was significantly suppressed by the administration of cupric acetate. The methylation of liver DNA in rats given a single dose of DMN was also significantly suppressed by sc injection of cupric acetate; the formation of both O6-methylguanine and 7-methylguanine was reduced. This result suggests that sc injection of cupric acetate may have a suppressive effect on the initiation of carcinogenesis in the liver.
The incidence of anti-adult T-cell leukemia-associated antigens (ATLA) was surveyed in 134 patients under chronic hemodialysis in the Nagasaki area, as well as 4708 blood donors resident in the same area as controls: 23 patients (17%) and 201 donors (4.3%) were positive for anti-ATLA antibody. All seropositive patients were found to have had a positive history of blood transfusions. Seroconversions were confirmed in 9 cases, all of them after initiation of transfusions. In total, 216 units of blood were transfused in 7 seroconverted patients, and this is consistent with the estimated rate of anti-ATLA antibody-positive donor blood supplied by the Red Cross Nagasaki Blood Center (5%).
The subcellular distribution of sialidase in rat hepatoma induced by 3'-methyl-4-dimethylaminoazobenzene was studied by using sialyllactose as a substrate in the pH range of 4.0-7.0. As found in rat liver, the activity was recovered largely in the mitochondrial/lysosomal fraction with an optimal pH of 4.5 and in the cytosolic fraction with an optimal pH of 6.0, although hepatoma lysosomal (acidic) sialidase was also distributed in the microsomal fraction. The lysosomal and cytosolic sialidases of the hepatoma were indistinguishable from the corresponding enzymes of liver in chromatographic behavior, kinetics and substrate specificity. The levels of lysosomal and cytosolic sialidase activities in liver and hepatomas were then studied in the pellet and supernatant fractions, respectively, obtained by centrifuging the postnuclear supernatant at 105, 000g for 1hr. All the hepatomas tested, one primary and three transplanted, showed higher lysosomal sialidase and lower cytosolic sialidase activities as compared with liver. Quantitative changes similar to those seen in hepatomas were observed in regenerating liver after partial hepatectomy.
The growth of rat ascites hepatoma cells (AH 66) in vitro was inhibited and the amount of α-fetoprotein (AFP) in the culture medium was increased in the presence of dibutyryl adenosine 3'-5' cyclic monophosphate (DBc-AMP). Electronmicroscopically, AH 66 cells that had been incubated with DBc-AMP showed an increase in polysomes on rough endoplasmic reticulum (RER), and some mitochondria appeared to be completely surrounded by RER. AFP in untreated cells was found to be localized on ribosomes of RER, free ribosomes and occasionally also on microvilli of cell membranes by electronmicroscopic and immunohistochemical analysis. After DBc-AMP treatment, increased staining of AFP was identified on ribosomes of RER and microvilli of cell membranes as well as on nuclear membranes. These results suggest that DBc-AMP accelerates the production and release of AFP in cultured rat ascites hepatoma cells.
Two distinct cell lines were obtained from a single heterotransplanted tumor which had originated from a primary focus of small cell carcinoma of the lung (SCCL). They were maintained separately from the beginning in culture media with and without fetal calf serum supplementation. Cells in the serum-free medium grew mostly floating in loose aggregates and showed poor cell cohesiveness, scanty cytoplasm and a few intracytoplasmic small dense-cored granules; all of these features are characteristics of oat cell type SCCL. On the other hand, cells in the serum-supplemented medium grew mostly floating in flatter and more closely associated clumps, were larger, and showed increased cell cohesiveness, occasional tubular structures, better developed organelles including dense-cored granules, and an increased number of cell attachments; these features are characteristics of intermediate cell type SCCL. The modal number of chromosomes differed from each other. Neuron-specific enolase (γ enolase) and aromatic L-amino acid decarboxylase (ADC) activities in cell pellets were significantly higher in both lines than in control non-small cell lung cancer cell lines. The α/γ type enolase ratio was lower, as was the ADC activity, in serum-free cultures than in serum-supplemented cultures. Interchange of the culture medium induced changes of the growth pattern and cell type from “oat cell type” to “intermediate cell type” and vice versa. The chromosomal number also partially changed. These findings suggest that cultured cells of SCCL alter their growth pattern and cell type depending on the culture conditions and that the selective growth of one cell type might then take place.
A novel human cultured cell line, P39/Tsugane, was established from leukemic cells in the peripheral blood of a 69-year-old male with overt leukemia following myelodysplastic syndrome (MDS). P39/Tsugane cells were characterized by blastic appearance, presence of NaF-sensitive α-naphthyl butylate esterase activity, Fcγ-receptor. C3-receptor, capacity to phagocytize sensitized erythrocytes, and reactivity with monoclonal antibodies such as OKT4, My4, VIMDS, MCS-2 and My7. These data indicate that P39/Tsugane cells are of myelomonocytoid nature. P39/Tsugane had a hypodiploid chromosome constitution with a gain of a consistent marker, 6q+, the presence of less consistent markers 9q+ and rep(14;16), and random and non-random losses of autosomes: in accordance with the reported cytogenetic profiles of MDS, a representative karyotype of the present cell line is 45, XY, +del(6)(q15), 9q+, t(14;16)-(q24;q21), -16, -17. P39/Tsugane cells were transplantable intraperitoneally into nude mice, and produced abdominal tumors and hemorrhagic ascites. These results indicate that P39/Tsugane is the first cultured cell line of myelomonocytoid nature to be derived from overt leukemia following MDS. Therefore, P39/Tsugane cells should be useful for studies on the differentiation of leukemia cells, the pathogenesis of MDS and in vitro-in vivo experimental chemotherapy.
T cells from 19 out of 25 childhood cancer patients showed impaired proliferative responses to purified protein derivatives (PPD)-pulsed antigen-presenting cells (APC) although all of the patients had been immunized with BCG. To test whether such low responsiveness of T cells results from the dysfunction of T cells or from that of APC, the experiment was designed to assess the proliferative response of T cells from patients or their parents to PPD-pulsed APC from patients or parents. These combinations seem to be suitable to assess the activity of T cells or APC since at least partial identity of HLA-D/DR antigens is required for T cell-APC interactions. Although T cells from patients who showed low responsiveness to PPD failed to respond even to PPD-pulsed APC from parents, T cells from parents were able to respond to PPD-pulsed APC from patients as well as to autologous APC. These observations strongly suggest that the low responsiveness to PPD in childhood cancer patients results from the dysfunction of T cells, and the capacity of APC is fully preserved. In other words, it appears that the capacity of APC is not impaired by chemotherapy, neoplastic cells, or other factors. Suppressor T cells appeared not to be involved in such dysfunction of T cells.
Growth-inhibitory activity of human recombinant β-interferon (GKT-β) against 20 human cultured cell lines derived from leukemias and lymphomas was measured quantitatively by regrowth assay. Daudi cells were the most sensitive to GKT-β. Two T-cell lines (RPMI-8402, HUT78), three B-cell lines (Raji, P3HR-1, A3/Kawakami), one non-T, non-B acute lymphoblastic leukemia (ALL) cell line (KOPN-1) and one monocytoid cell line (U937) were moderately sensitive to GKT-β. Although the levels of sensitivity of these cell lines to GKT-β were different, the cells could be killed by GKT-β. Morphological changes of the sensitive cells treated with GKT-β were decrease in mitosis, pyknosis and segmentation of cells. Twelve other cultured cell lines, comprising four T-cell lines, four B-cell lines, one non-T, non-B ALL cell line and three myelomonocytoid cell lines, were not sensitive to GKT-β. The results indicated that the growth-inhibitory activity of GKT-β was not always cell lineage-specific or differentiative stage-specific. GKT-β was instable in vitro and its antiviral activity was reduced to about 10% during the first 24hr of incubation in culture medium with or without cells. This instability was reflected in a similar reduction of its growth-inhibitory activity. It was demonstrated that GKT-β had a time-dependent, but not a concentration-denpendent antiproliferative action. This suggests that, in the clinical use of the interferon, direct antiproliferative activity of GKT-β may be expected only through the use of therapeutic schedules which are suitable for its time-dependent action, such as through daily long-term treatment, but not through a single large-dose therapy.
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