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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.

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 beta-interferon (GKT-beta) 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-beta. 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-beta. Although the levels of sensitivity of these cell lines to GKT-beta were different, the cells could be killed by GKT-beta. Morphological changes of the sensitive cells treated with GKT-beta 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-beta. The results indicated that the growth-inhibitory activity of GKT-beta was not always cell lineage-specific or differentiative stage-specific. GKT-beta was instable in vitro and its antiviral activity was reduced to about 10% during the first 24 hr 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-beta 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-beta 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.

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.

The effect of cupric acetate on dimethylnitrosamine (DMN)-induced hepatocarcinogenesis in rats was investigated. The surviving rats in the group given DMN (25 ppm) 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 2 mg 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.

Optimal conditions for the in vitro production of cytotoxic lymphocytes against autologous lung cancer cells were studied. In the time-course experiments, fresh lymphocytes did not exhibit any cytotoxicity against autologous tumor cells, but, when cultured in the presence of T cell growth factor (IL2), the lymphocytes became cytotoxic against autologous tumor cells 3 days after the initiation of incubation and the cytotoxicity continued to increase, reaching a maximum at day 7. The study, conducted to compare the effects of IL2 and phytohemagglutinin (PHA), demonstrated that although lymphocytes cultured with PHA did exhibit a significant cytotoxicity, lymphocytes cultured with IL2 showed much higher activity. Peripheral blood, regional lymph node (RNL) and distal lymph node lymphocytes, and tumor infiltrating lymphocytes were tested as sources for the production of cytotoxic lymphocytes. Among these 4 sources, RNL proved the most consistently reliable source of cytotoxic lymphocytes. The results of in vitro stimulation by autologous tumor cells were ambivalent. Twenty-five experiments that compared in vitro stimulation by tumor cells and no stimulation revealed that 9 cases (36%) showed enhancement of cytotoxicity after stimulation with tumor cells, 5 cases showed inhibition, and the remainder no effect. Characterization of lymphocytes by using monoclonal antibodies indicated that cells lytic for autologous tumor cells are OKT3+, OKT8+, OKT4-, OKM1-.

Dialyzed urine of mice bearing leukocytosis-inducing fibrosarcoma stimulated granulocyte colony formation in semisolid agar culture of human bone marrow cells. Removal of phagocytic cells prior to stimulation did not interfere with the formation of these colonies in the culture. On the other hand, macrophage colonies were predominantly produced when murine bone marrow cells were stimulated by the dialyzed mouse urine. The activity of colony-stimulating factor (CSF) in the urine of normal mice was less than 1/100 of that in the urine of tumor-bearing mice. DEAE-cellulose column chromatography separated the activity stimulating human granulocyte colony formation from that stimulating murine macrophage colony formation. Further purification showed that a sialoglycoprotein with an apparent molecular weight of 80,000 corresponded to the macrophage CSF, which was devoid of activity toward human cells. The molecular properties of the human-active granulocyte CSF could not be studied further, because it was quite unstable.

A microplate leukocyte adherence inhibition (micro-LAI) assay was performed with peripheral blood mononuclear cells obtained from patients with hepatoma and control subjects (including healthy donors and patients with other diseases). Cell extracts of human hepatoma cells (HCC-M) and human hepatic cells (Chang liver cell) in tissue culture were prepared by sonication followed by centrifugation. The supernatants of these two cell lines were used as a specific antigen and a nonspecific antigen, respectively. It was found that monocytes were major indicator cells and that monocytes produced an LAI reaction in the absence of lymphocytes. Therefore, a repeated microplate monocyte adherence inhibition (MAI) assay was developed, in which the monocyte population of adherent cells is increased by removing nonadherent cells after an initial assay in fetal calf serum-containing medium without test antigens, and monocytes are counted selectively as peroxidase-positive cells in a subsequent second assay with test antigens. With regard to sensitivity and reproducibility, the repeated micro-MAI assay is superior to a micro-MAI assay in which the initial assay is omitted although monocytes are selectively counted. With this simple and sensitive technique a hepatoma-associated immune response to the extract of HCC-M was detected in 16 out of 22 patients (73%) with hepatoma, whereas the false-positive rate was 7% (3/41) in all control subjects.

Expression of heterophile Hanganutziu-Deicher (HD) antigen on the cell surface of various human malignant tumor tissues was studied by membrane immunofluorescence staining with chicken antiserum against N-glycolylneuraminyllactosylceramide (HD3) and fluorescein-conjugated rabbit anti-chicken IgG. The HD antigen was demonstrated in samples from 38 of 77 (38/77, 49%) cases, consisting of gastric (9/16), breast (8/14), colorectal (3/12), nasopharyngeal (4/7), and uterine (2/3) carcinomas, leukemias (5/10), malignant lymphomas (2/5), and other cancers (5/10). Histological examination indicated that expression of the antigen by the gastric, colorectal and breast carcinomas and leukemias was not related to their histological types. The cytoplasm and the surface of the malignant glandular epithelial cells were both specifically stained by immunofluorescence staining of frozen sections in one colon adenocarcinoma. Glycosphingolipids (GSLs) were extracted from the colon cancer tissue and two HD antigen-active GSLs were detected on thin-layer chromatography (TLC) by enzyme-immunostaining using affinity-purified chicken anti-HD3 and horseradish peroxidase-conjugated rabbit anti-chicken IgG. One migrated to the same position as HD3 on TLC, and the other to a position similar to that of authentic N-glycolylneuraminylneolactotetraosylceramide.

Summation and synergism in the effects of three tumor promoters on urinary bladder carcinogenesis initiated by a 4-week treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats were examined. In experiment 1, the sequential administration of sodium saccharin (SS, 5.0%), DL-tryptophan (Tr, 2.0%) and sodium L-ascorbate (SA, 5.0%) in the diet, each for 10 weeks, significantly increased the incidence and the number of bladder tumors over that observed after SS alone or SS followed by Tr. In experiment 2, the simultaneous dietary administration of 2.5% SA, 1.0% butylated hydroxyanisole and 0.01% allopurinol for 32 weeks significantly increased the yield of bladder tumors. Paired combinations of promoters or each of the promoters administered alone were associated with a less pronounced promotive effect than when all three were combined. Thus, it is evident from the results of the present investigation that whatever the mechanisms underlying promotion by the different agents, they are capable of working in an additive fashion, under conditions of summation (consecutive administration) or synergism (simultaneous administration).