PubMed Health⌕ Search

Biomedical subjects

M Yagita

Publications and source records attributed to M Yagita.

At least 19 recordsLinked to original sources
PubMed1998

Therapy-related leukemia and myelodysplasia following oral administration of etoposide for recurrent breast cancer.

We report a high risk of therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) in patients receiving oral administration of etoposide for recurrent breast cancer. We examined 119 patients with recurrent disease. Patients were initially treated with anthracyclines, cyclophosphamide, or cisplatin with or without radiation before etoposide treatment. Etoposide was used as the final drug in most cases. Twenty-four patients were treated with the oral administration of etoposide (50 or 100 mg/day for 5-7 days at 4-week intervals). Three cases of t-AML/MDS developed among those 24 patients exposed to etoposide. In contrast, the development of t-AML/MDS was not observed in the other 95 patients not treated with etoposide. Our data suggest that there is a substantial risk of secondary leukemia with oral administration of etoposide for a prolonged period as well as i.v. schedules.

Administration, Oral↗
PubMed1998

[Extramedullary relapse in the external auditory canal in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid and autologous peripheral blood stem cell transplantation].

A 41-year-old man was given a diagnosis with of acute promyelocytic leukemia (APL) in August 1994. A chromosome analysis showed 46, XY, t(15; 17) and 47, XY, idem, +8 at that time. Because initial induction chemotherapy (BHAC-DMP) has not been successful, the patient was given 45 mg/m2 of all-trans retinoic acid (ATRA) and achieved complete remission (CR) after 26 days on this regimen. Following intensified chemotherapy, he received an autologous peripheral blood stem cell transplant (PBSCT) with high-dose busulfan and cyclophosphamide in April 1995. Competitive RT-PCR for PML-RAR alpha mRNA did not find any of APL cells in the collected stem-cell fraction. Although the patient remained in CR without therapy, a myeloblastoma was found in his left external auditory canal in August 1996. Recurrence in bone marrow, moreover, was discovered the following month. A chromosome analysis of bone marrow cells showed 47, XY, t(15; 17), +8 at this time. Thus, the extramedullary relapse developed after autologous PBSCT. This case provides information linking ATRA to the development of extramedullary relapse in patients with APL.

Adult↗
PubMed1995

Heat shock enhances the susceptibility of tumor cells to lysis by lymphokine-activated killer cells.

OBJECTIVE: To determine whether heat-treated thyroid cancer cells augment the susceptibility of target cells to lysis by autologous lymphokine-activated killer cells. DESIGN: Peripheral blood lymphocytes from patients with thyroid cancer were incubated with recombinant interleukin 2 (100 U/mL) for 7 days, and thyroid cancer cells obtained from surgical specimens were heated at 44 degrees C for 20 minutes and incubated at 37 degrees C for 18 hours before performing the radioactive chromium Cr 51 release assay. RESULTS: The susceptibility of heat-treated thyroid cancer cells to lysis by autologous and allogeneic lymphokine-activated killer cells was significantly greater than that of untreated tumor cells. The mechanism of enhanced susceptibility was unclear. However, the effect depended on de novo protein synthesis, because inhibition of RNA synthesis by dactinomycin completely abolished the heat-enhanced susceptibility of tumor cells. CONCLUSION: Immunotherapy combined with hyperthermia may be useful in management of thyroid cancer.

Adenocarcinoma, Papillary↗
PubMed1994

Swainsonine augments the cytotoxicity of human lymphokine-activated killer cells against autologous thyroid cancer cells.

OBJECTIVE: Swainsonine (SW), an inhibitor of mammalian Golgi alpha-mannosidase II, blocks the processing of high mannose to complex type oligosaccharides. In this study, the effect of SW on the cytotoxicity of lymphokine-activated killer (LAK) cells against autologous thyroid cancer was investigated. DESIGN: Peripheral blood lymphocytes from patients with thyroid cancer were incubated with recombinant interleukin 2 (100 U/mL) and 0.5 mg/L of SW for 7 days, and thyroid cancer cells obtained from surgical specimens were pretreated with SW (0.5 mg/L) for 18 hours. The cytotoxicity of SW-treated LAK cells against tumor cells tested in a standard 4-hour radioactive chromium Cr 51 release assay. RESULTS: The cytotoxicity of SW-treated LAK cells against autologous thyroid cancer cells was found to be significantly greater than that of standard LAK cells incubated with interleukin 2 alone. The N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester esterase activity of LAK cells, this activity being a cytotoxic factor that is necessary for the lethal hit stage, was also increased by SW treatment. Further, thyroid cancer cells incubated with SW, as compared with nontreated tumor cells, showed much higher susceptibility to LAK killing. CONCLUSIONS: Our results suggest that SW might have potential immunomodulatory properties in the treatment of thyroid cancer.

Adenocarcinoma, Papillary↗
PubMed1993

Deacetylase activity of human tumor cells producing immunosuppressive aminosugars: its possible role in resistance to cell-mediated cytotoxicity.

In the present study, we examined the presence of deacetylases capable of producing free hexosamines, which we have shown earlier to be immunosuppressive against human natural killer (NK) cell-mediated cytotoxicity, from N-acetylhexosamines in human tumor cells. When human NK-resistant colon cancer cells (Colo-320DM) were incubated with acetyl-D-[1,6-3H(N)]glucosamine, a significant conversion to [3H]glucosamine occurred. Deacetylation was demonstrated as a change of the substrate radioactivity into free glucosamine trapped by a cation exchange resin, and this was subsequently confirmed by paper chromatography. This deacetylase activity was detected in other NK-resistant tumor cell lines, especially in freshly isolated human renal and breast cancer cells and testicular seminoma cells. However, no deacetylase activity was detected in NK-sensitive target cells such as K562, MOLT-4, or HL-60 cells. The ability to produce free hexosamines from N-acetylated aminosugars may provide a new mechanism for the escape of tumor cells from the attack of immune effector cells such as NK cells.

Acetylglucosamine↗
PubMed1993

Dimethyl sulfoxide (DMSO) increases expression of sialyl Lewis x antigen and enhances adhesion of human gastric carcinoma (NUGC4) cells to activated endothelial cells.

Dimethyl sulfoxide (DMSO) exerts a number of biological effects including the promotion of cell differentiation in cultured cells. In this study, we examined the effect of DMSO on the adhesion of tumor cells to endothelial cells. In vitro treatment of human gastric adenocarcinoma (NUGC4) cells with DMSO resulted in increased adhesion to interleukin-I (IL-I)-activated human endothelial cells compared with DMSO-untreated NUGC4 cells. In flow cytometry, treating NUGC4 cells with DMSO enhanced the expression of sialyl Lewis x (sialyl Le(x)) and sialyl dimeric Le(x) antigens on their surface. Also, the binding of Limulus polyphemus agglutinin (LPA), which specifically binds to cell-surface sialic acids, was increased by DMSO. The adhesion of DMSO-treated NUGC4 cells to activated endothelial cells was blocked by neuraminidase pre-treatment of tumor cells or by antibody against either endothelial leukocyte adhesion molecule-I (ELAM-I) or sialyl Le(x). Thus, it is suggested that enhanced adhesion following DMSO treatment is mediated by the interaction of sialyl Le(x) expressed on NUGC4 cells with ELAM-I of endothelial cells. The modulation of sialyl Le(x) antigen by DMSO provides a useful system for studying the regulatory mechanism of Lewis-related carbohydrate antigens and also for understanding the metastatic properties of cancer cells.

Antibodies, Monoclonal↗
PubMed1992

The presence of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells: their possible role in swainsonine-augmented human NK cytotoxicity.

In the present study we examined the expression of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells and investigated their possible role in the human NK-cell phenomenon. The incubation of either peripheral-blood lymphocytes (PBL) or large granular lymphocytes (LGL) with swainsonine (SW), an inhibitor of mannosidase II, resulted in the augmentation of cytotoxicity against K562 leukemia cells. The enhanced cytotoxicity was associated with increased binding of fluorescein isothiocyanate-conjugated Con-A to SW-treated effector cells, and immunofluorescence staining of the target K562 cells using goat anti-Con-A antibody (Ab) showed a significant positive shift in the flow cytometric pattern. Electrophoretic separation and immunoblotting analysis revealed that 4 components with a molecular weight of approximately 95, 80, 60 and 50 kDa were recognized by anti-Con-A Ab from the detergent-extract of K562 cells. The addition of Con-A during the antibody incubation step of the Western blotting abolished their expression, thus excluding non-specific binding of the antibody. The addition of Con-A also strongly inhibited the cytotoxicity of SW-treated effector cells (PBL or LGL) against K562 cells, and this inhibition was abolished by 40 mM alpha-methyl-mannopyranoside (alpha-MM), which binds to Con-A. Furthermore, Con-A increased the binding frequency of SW-treated LGL to K562, in spite of the inhibited cytotoxicity, and this effect could be neutralized by the further addition of alpha-MM. Our results suggest that Con A-like molecules might play an important role in cell-cell interactions between SW-treated effector cells and NK target cells.

Adenosine Triphosphate↗
PubMed1991

Lysis of fresh human tumor cells by autologous peripheral blood lymphocytes and tumor-infiltrating lymphocytes activated by PSK.

The protein-bound polysaccharide PSK was tested for the ability to induce in vitro autologous tumor killing (ATK) activity in human cancer patients. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) demonstrated various levels of cytotoxicity against autologous, freshly isolated tumor cells. When PBL and TIL were cultured overnight with PSK, ATK activity was induced in previously non-reactive cases and augmented in previously reactive samples. The PSK effect was observed with PSK concentrations of 10-100 micrograms/ml that could be obtained in the blood of cancer patients who received standard oral administration of PSK. The manifestation of PSK-induced ATK required active cell metabolism and RNA and protein syntheses, but not DNA synthesis of lymphocytes. PSK-induced enhancement of ATK was not abrogated by monoclonal antibodies (mAb) directed against interferon (IFN) alpha or IFN gamma. In addition, mAb that neutralized interleukin-2 (IL-2) or mAb reactive with alpha-chain or beta-chain of IL-2 receptors (IL-2R) had no effect on PSK-induced ATK activity. Supernatants from PSK-stimulated lymphocyte cultures did not induce ATK. Cell fractionation experiments revealed that CD3-CD16+ large granular lymphocytes (LGL) and/or CD3+CD16- T lymphocytes were responsible for both spontaneous and PSK-induced ATK. PSK-activated LGL, but not T lymphocytes expressed lysis of fresh allogeneic tumor cells. These results indicate that PSK activates PBL and TIL to exhibit ATK independently of IL-2/IL-2R systems.

Adult↗
PubMed1990

Prediction of postoperative clinical course by autologous tumor-killing activity in lung cancer patients.

Fifty patients with primary localized lung cancer were tested at the time of surgery for the ability of their lymphocytes to kill autologous, freshly isolated tumor cells, and the assay was evaluated for prognostic significance. Peripheral blood lymphocytes of 27 patients (54%) demonstrated significant autologous tumor-killing activity in 6-hour 51Cr-release assays. Twenty-three of the 27 patients with autologous tumor-killing activity remained tumor free and survived more than 5 years after curative surgery, while all 23 who were negative for autologous tumor-killing activity relapsed by 18 months after surgery and died within 42 months after surgery. The differences in survival curves for the two groups were highly significant (P less than .00003). Autologous tumor-killing activity was not correlated with natural killer (NK) cell activity against K562 human myeloid leukemia cells or proliferation of lymphocytes stimulated with autologous, freshly isolated tumor cells in mixed culture. There were no differences in total survival between patients with positive results and those with negative results in tests of NK cell activity and autologous mixed lymphocyte-tumor culture reaction. These results indicate that autologous tumor-killing activity is a meaningful prognostic indicator and provide evidence for immunological control of tumor growth and metastasis. According to our preliminary data, it is unlikely that lung cancer patients who remain tumor free after 60 months of follow-up will develop recurrence or die from the disease. We are conducting a study to determine whether induction of autologous tumor-killing activity before surgery, by treatment with biological response modifiers,can improve the clinical outcome in patients who do not naturally have this potential.

Adult↗
PubMed1990

Soluble factor in normal tissues that stimulates high-molecular-weight sialoglycoprotein production by human colon carcinoma cells.

The stimulation of high molecular weight sialoglycoprotein synthesis by a soluble factor derived from normal colon tissues was studied in vitro with human colon carcinoma cell lines, HT-29 P and a metastatic variant HT-29 LMM. The synthesis of all three high-molecular-weight sialoglycoproteins (approximate Mr 900,000, 740,000, and 450,000) by HT-29 P cells or HT-29 LMM cells growing in vitro was enhanced by supplementing the culture medium with a conditioned medium of fresh human colon organ culture. Changes were detected by polyacrylamide gel electrophoresis of lysates from [3H]glucosamine-labeled cells on 3% gels followed by fluorography, or by electrophoresis of lysates from unlabeled cells followed by incubation with 125I-labeled wheat germ agglutinin and autoradiography. No changes were detected in the major protein components or in glycoproteins at Mr less than 200,000 as revealed by polyacrylamide gel electrophoresis. The treated cells did not change their growth rate or morphology. The connective tissue portions of the colon tissues were apparently responsible for the production of this stimulatory substance. The stimulatory activity was preserved at 56 degrees C but was inactivated by heating at 100 degrees C. The substance was eluted from a Sephacryl S-200 column at a position between the elution positions of ovalbumin and trypsinogen. The colon carcinoma cells treated with the conditioned medium and producing increased amounts of high-molecular-weight sialoglycoproteins were less sensitive to the cytolytic effects of recombinant interleukin 2-activated human peripheral blood lymphocytes than untreated cells were. The treated colon carcinoma cells induced stronger platelet aggregation than their untreated counterparts did. Therefore, this substance may represent one of the normal host tissue factors that can influence and modulate malignant behavior of carcinoma cells growing in vivo.

Cell Division↗
PubMed1990

Reduction by OK-432 of the monolayer contact-mediated inhibition of human natural killer cell activity.

In the present study we investigated the effect of OK-432, a streptococcus preparation, on the contact-mediated inhibition of human NK activity by primary cultures of monolayer cells. Either peripheral blood lymphocytes (PBL) or large granular lymphocytes (LGL) were incubated (2 x 10(6) cells/ml, total volume 2 ml) on confluent monolayer cells (uvea-derived fibroblasts, uvea-derived melanoma cells, or renal carcinoma cells) for 18 h in 24-well plates, washed twice, and tested for cytotoxicity against K562, a human myelogenous leukemia cell line, in a 4 h 51Cr-release assay. After contact with monolayer cells, NK activity of both PBL and LGL was significantly reduced. When these effector cells were preincubated with 0.1 U/ml of OK-432 for 18 h and then tested for the sensitivity to contact-mediated inhibition, the inhibition was significantly reduced. The pretreatment of monolayer cells with OK-432 or the addition of OK-432 into the coculture wells (of effector cells and monolayer cells) also significantly reduced the contact-mediated inhibition. Moreover, OK-432 (0.1 U/ml) reestablished the inhibited NK activity of PBL. These results suggest that OK-432 might enable NK cells to escape from the contact-mediated inhibition by monolayer cells and thus provide an additional potential mechanism for the observed clinical effectiveness of OK-432 reported by many groups.

Adenosine Triphosphate↗
PubMed1990

Swainsonine, an inhibitor of glycoprotein processing, enhances cytotoxicity of large granular lymphocytes.

In the present study we investigated the effects of inhibitors of glycoprotein processing on cytotoxicity of human large granular lymphocytes (LGL). The incubation of LGL for 36 h with 0.5 microgram/ml swainsonine (SW), which is an inhibitor of mannosidase II, resulted in the augmentation of cytotoxicity of LGL against an NK-resistant colon carcinoma cell line (Colo-320DM) without increase of binding frequency of LGL to target cells or of cell proliferation. The enhanced cytotoxicity was associated with increased binding of concanavalin A to SW-treated LGL. The augmentation of cytotoxicity was also seen by 1-deoxymannojirimycin (1-DMN), an inhibitor of mannosidase I, but much higher amounts of this agent were needed to get the same level of augmentation as that with SW. Other inhibitors of glycoprotein processing such as castanospermine and 1-deoxynojirimycin (1-DN) did not show any augmentative effects on LGL cytotoxicity. The enhancement of cytotoxicity by SW was abolished by the addition of rabbit anti-human interleukin (IL-2) antibody to the culture. This result suggests that IL-2 is involved in the augmentation of cytotoxicity of LGL by SW. The presence of SW in the culture of LGL together with IL-2 also enhanced LAK generation compared to that with IL-2 alone. Thus, our results suggest that SW should be recognized as an efficient immunopotentiator and that modulation of carbohydrate moieties elicited by SW may shed further light on the mechanism of LGL activation.

Alkaloids↗
PubMed1989

Involvement of both Tac and non-Tac interleukin 2-binding peptides in the interleukin 2-dependent proliferation of human tumor-infiltrating lymphocytes.

Interleukin 2 (IL-2) receptor expression was examined on recombinant IL-2 (rIL-2)-propagated tumor-infiltrating lymphocytes (TIL) from eight metastatic melanoma and three sarcoma samples. All 11 TIL expanded with similar growth rates. rIL-2 propagated TIL from five of eight metastatic melanoma specimens contained no Tac antigen-positive lymphocytes as determined by immunofluorescence and flow cytometry performed multiple times during the 4 to 8 week culture period. However, "Tac-negative" TIL did express the non-Tac IL-2-binding peptide, p70-75 as determined by [125I]IL-2 cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IL-2-binding assays revealed that these "Tac-negative" TIL expressed only an intermediate affinity IL-2 receptor. In contrast, TIL from the other three of eight melanoma and all three sarcoma contained one-third Tac-positive cells as assessed by flow cytometry analysis, and expressed surface non-Tac (p70-75) and Tac (p55) peptides by [125I]IL-2 cross-linking. These "Tac-positive" TIL displayed both the high and intermediate affinity IL-2 receptors. However, rIL-2-dependent growth of both "Tac-negative" and "Tac-positive" TIL was significantly inhibited by anti-Tac mAb, suggesting a transient Tac expression on the "Tac-negative" TIL. Additionally, due to the limits of our methodology, we cannot rule out the possibility of a constitutive expression of a low level of Tac, with an indicible expression of higher levels. Addition of culture supernatants from phytohemagglutinin- and phorbol myristate acetate-stimulated peripheral blood mononuclear cells to the "Tac-negative" TIL-induced detectable Tac expression within 48 h. These results indicate that both non-Tac and Tac IL-2 receptors play important roles during IL-2-dependent proliferation of TIL.

Antibodies, Monoclonal↗
PubMed1989

Suppression of human natural killer cell activity by amino sugars.

In the present study we investigated the effect of amino sugars on human natural killer (NK) activity against K562, a human myeloid leukemia cell line, and Molt-4, a human T lymphoma cell line. The presence of amino sugars such as D-mannosamine, D-galactosamine, and D-glucosamine [6-25 mM (in the case of D-mannosamine, 1.5-12.5 mM)] in a 4-hr chromium-51 (Cr) release assay significantly inhibited NK activity of large granular lymphocytes (LGL) without affecting effector cell viability or spontaneous release from target cells. Sugars with acetylated amino residues (N-acetyl-D-mannosamine, N-acetyl-D-galactosamine, and N-acetyl-D-glucosamine) showed much smaller NK inhibition. Among the amino sugars tested, D-mannosamine was the strongest suppressor. When either LGL or K562 cells were pretreated with amino sugars and used in the 4-hr 51Cr release assay, only the pretreatment of effector cells resulted in the reduction of NK activity. The binding capacity of LGL to K562 cells, determined by a conjugate assay, was not reduced by the amino sugars enough to explain the strong inhibition of NK activity by these amino sugars, although some inhibitory effect on the binding of LGL to K562 cells was observed in some cases. In contrast, the polarization of the effector cell cytoskeleton, one of the energy-dependent steps, was significantly impaired. The cellular ATP level of LGL was also significantly reduced and the reduction of cellular ATP correlated well with the degree of the inhibition of NK cytotoxicity. These results suggest that the suppression of NK activity by amino sugars is due to the reduction of the ATP-based energy supply of the effector cells and that amino sugars, especially D-mannosamine, should be recognized as potent suppressors of natural cell-mediated immunity.

Adenosine Triphosphate↗
PubMed1988

[Effect of histamine H2-antagonists on serum gastrin levels in gastric lumen-perfused rats].

The effect of histamine H2-antagonists on serum gastrin concentration and histamine-stimulated gastric acid secretion was studied in gastric lumen-perfused rats in which changes in the intragastric pH were limited by using 2.5 mM propionate-succinate buffer as perfusate. The gastric acid secretion was measured by the titration of the acidity of gastric juice with 0.05 N NaOH. The serum gastrin levels were determined in the blood that was obtained simultaneously with gastric juice by radioimmunoassay. The gastric acid secretion was inhibited by these histamine H2-antagonists--cimetidine, famotidine, ranitidine and TZU-0460 administered intravenously. Within the dose-response range of the inhibition of gastric acid secretion, cimetidine and ranitidine increased significantly the serum gastrin levels, but famotidine and TZU-0460 did not. The doses of famotidine and TZU-0460 which were used to increase the serum gastrin levels were found to be higher than those for the maximal inhibition of gastric acid secretion. They also presented a dose-response curve to the serum gastrin levels similar to cimetidine and ranitidine. The findings suggest that histamine H2-antagonists have a potency to increase serum gastrin levels to that of the inhibition of gastric acid secretion.

Animals↗
PubMed1988

Functional differentiation of human lymphokine-activated killing (LAK) is distinct from expansion and involves dissimilar interleukin 2 receptors.

Human lymphocytes respond to IL-2 with the generation of MHC-unrestricted oncolytic activity. This function has been named lymphokine-activated killing (LAK). To investigate the mechanism by which IL-2 activates and maintains LAK, we have examined the role(s) of IL-2 cell surface receptors. Removal or blockade of unstimulated lymphocytes expressing the IL-2 receptor Tac does not preclude the acquisition of LAK function. Therefore, a non-Tac IL-2 receptor was proposed to be involved in LAK generation. Using direct 125I-IL-2 binding to Tac-negative LAK precursors suggested the existence of such an alternate IL-2 receptor. Chemical crosslinking of 125I-IL-2 to Tac-depleted lymphocytes followed by SDS-PAGE determined that the size of the non-Tac-binding protein was approximately 75 kDa. Tac-negative lymphocytes activated by a limited IL-2 pulse which was insufficient for detectable Tac upregulation indicated that an initial non-Tac pathway was involved in functional differentiation. The development of lytic function, Tac upregulation, and cellular proliferation was prohibited by trypsin, a treatment shown also to eliminate 125I-IL-2 binding to Tac-negative lymphocytes. The Tac antigen, although not involved in the initial generation of LAK, is involved in the proliferative maintenance of this lytic function.

Cell Differentiation↗