[A case report of testicular torsion (author's transl)].
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Adolescent↗
Biomedical subjects
Y Nio
Publications and source records attributed to Y Nio.
[Studies on the cells producing an antitumor agent].
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Animals↗
In vitro production of an antitumor agent by reticuloendothelial cells.
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Animals↗
Second malignancies after a gastrectomy for gastric cancers: the effects of adjuvant therapies.
Second malignancy after gastrectomy has become one of the important issues in the management of gastric cancer patients. However, the effect of adjuvant therapies has never been surveyed, although there have been many reports on second malignancy after chemotherapy of other malignancies. Between 1979 and 1995, 574 patients with gastric cancer underwent gastrectomies in our department. 563 patients (98.1%) were completely followed-up, and the incidence of second malignancy after gastrectomy was assessed with special emphasis on the effect of adjuvant therapies, namely benefits versus carcinogenesis. The overall postsurgical survival rate was 62.5%, and the survival rate of patients with stage 2-4 cancer was significantly higher in the adjuvant therapy groups than in the surgery alone group. The overall incidence rate of a second malignancy was 3.20% (18/563), including 4 colorectal, 3 liver, 3 head and neck, and 8 other malignancies, and 3.90% (9/231) for the surgery alone group, 1.94% (3/155) for the chemotherapy group, 3.68% (6/163) for the chemoimmunotherapy group, and 0% (0/14) for the immunotherapy alone group. There were no statistical differences in the incidence rates between these 4 groups. The mean duration until the occurrence of second malignancy was 5.1 years for the surgery alone group, 8.6 years for the adjuvant therapy group (9.3 years for chemotherapy and 8.1 years for chemoimmunotherapy; p < 0.1, surgery alone vs. adjuvant therapy). The overall mean actuarial risk of developing a second malignancy was 6% at 5 years and 18% at 10 years. Multivariate analysis demonstrated that chemotherapy decreased the risk of death due to gastric cancer (risk ratio = 0.67, p = 0.017) and the risk of a second malignancy (risk ratio = 0.52, p = 0.261). Oral fluoropyrimidines were found to be particularly effective at decreasing the risk of death due to gastric cancer (risk ratio = 0.66, p = 0.012) and a second malignancy (risk ratio = 0.38, p = 0.136). However, intravenous chemotherapy was demonstrated to have no influence on survival (risk ratio = 0.93, p = 0.692) or a second malignancy (risk ratio = 0.58, p = 0.500). There was no evidence of an increased risk for a second malignancy following adjuvant chemotherapy. Adjuvant chemotherapy with oral fluoropyrimidines was suggested to contribute to the improved survival of patients with stage 2-4 gastric cancer, and to have a decreased the risk of a second malignancy.
Adult↗
Human proinsulin gene-transfected Chinese hamster ovary cells secrete immunoreactive insulin.
BACKGROUND: Considering the difficulties in pancreas transplantation, the development of an artificial pancreas can be one of the new approaches. The present study was designed to assess whether or not Chinese hamster ovary (CHO) cells, which were transfected with the human proinsulin (hPI) gene, secrete immunoreactive insulin (IRI) and respond to glucose loading. MATERIALS AND METHODS: A complementary DNA encoding hPI was obtained by polymerase chain reaction amplification from human pancreatic tissue and was inserted into the plasmid pcDNA I/NEO to construct an expression vector for the hPI gene. CHO cells were transfected with hPI gene using lipofectin, and the hPI gene-expressing clones (CHO/I) were selected. RESULTS: Five clones of CHO/I cells, releasing IRI into the culture supernatant, were separated. Immunohistochemistry with a monoclonal antibody demonstrated the IRI in the cytoplasm of CHO/I cells, and transmission electron microscopic examination demonstrated the prominently developed mitochondria, but no secretion granules. ELISA assay demonstrated the secretion of IRI into the culture supernatant of CHO/I, but CHO/I cells did not respond to the glucose loading. When CHO/I cells were transplanted subcutaneously into the back of nude mice, the growing tumors secreted IRI. CONCLUSIONS: These results demonstrate that the hPI gene can be transfected into mammalian cells and function in vivo, and suggest that this kind of gene technology may be applicable in the development of an artificial pancreas.
Animals↗
Anticancer chemosensitivity profiles of human breast cancer cells assessed by in vitro DNA synthesis inhibition assay.
The present study was designed to assess the profile of the chemosensitivity of breast cancer cells and to screen effective agents for combination regimens. Chemosensitivity to anticancer agents was assessed by the 3H-thymidine incorporation assay, as the rate of inhibition of DNA synthesis in 145 samples (88 primary and 57 metastatic or recurrent lesions) from 136 patients with breast cancer. The correlations of the anticancer agents with various clinicopathological factors were analysed. The effectiveness of the agents was classified as a rate of inhibition on log scale as follows: highly sensitive (> or = 30%), moderately sensitive (25-30%), slightly sensitive (20-25%), resistant (< 20%). The chemosensitivity of breast cancer showed variations according to tumor location: primary lesions seemed to be slightly sensitive to carboquone (CQ), adriamycin (ADR), and cytosine arabinoside (Ara-C); nodal involvement was moderately sensitive to CQ and slightly sensitive to Ara-C, 5-FU, ADR, mitomycin-C (MMC), and cisplatin (CDDP); malignant effusions were highly sensitive to ADR, moderately sensitive to CQ, and slightly sensitive to Ara-C and CDDP; local recurrences were slightly sensitive to Ara-C, CQ and 5-FU; vincristine (VCR) and nimustine chloride (ACNU), however, seemed to be ineffective against breast cancer. There were significant correlations in chemosensitivity between most agents, but no correlation was found between 5-FU and CDDP, 5-FU and ACNU, MMC and VCR, ADR and CDDP, ADR and VCR, and ADR and ACNU. There were no differences in chemosensitivity between stages of primary lesions or between estrogen receptor-positive and -negative tumors. In 10 patients, simultaneous nodal involvement was more sensitive to the agents than were primary lesions, and the correlation of chemosensitivity to ADR and CQ between such lesions was significant. On the other hand, there was no significant difference or correlation of chemosensitivity between the original lesions and recurrent ones after chemotherapy. The heterogeneity and homogeneity in the chemosensitivity of breast cancer suggested not only the necessity of patient-specific chemotherapy based on a sensitivity assay, but also the usefulness of choosing agents for widely-applicable combination regimens against breast cancer.
Adult↗
Intraperitoneally implanted artificial pancrease with transkaryotic beta-cells on microcarrier beads in a diffusion chamber improves hyperglycemia after 90% pancreatectomy in rats.
BACKGROUND: Considering the difficulties in pancreas transplantation, the development of an artificial pancreas would be of great value. We have established a transkaryotic artificial beta-cell line, CHO/I, produced by transfecting the human proinsulin gene into the Chinese hamster ovary (CHO) cell line. The present study was designed to assess the value of an artificial pancreas using a diffusion chamber containing CHO/I cells. MATERIALS AND METHODS: Wistar rats rendered diabetic by 90% pancreatectomy were treated by implanting a diffusion chamber containing CHO/I cells cultured on microcarrier beads. RESULTS: The diffusion chamber containing microcarrier beads produced 100-folds more CHO/I cells than the chamber alone, as calculated from the secreted IRI in vitro. When diffusion chambers containing CHO/I cells on microcarrier beads were implanted into the peritoneal cavity of the 90% pancreatectomized rats, the fasting serum IRI level increased and the fasting blood glucose decreased to the normal level for 12 weeks. An intraperitoneal glucose tolerance test demonstrated, however, that the diffusion-chamber-implanted rats did not respond to glucose loading. CONCLUSION: An artificial pancreas using a diffusion chamber containing human proinsulin gene transfected cells might be a promising model for future clinical application.
Animals↗
Reduced invasiveness and metastasis of Chinese hamster ovary cells transfected with human interleukin-17 gene.
Human IL-17 (hIL-17) stimulates epithelial, endothelial, fibroblastic cells and macrophages to secrete various cytokines. The present study was designed to assess the effects of the transfection of the hIL-17 gene in Chinese hamster ovary (CHO) cells. A complementary DNA (cDNA)-encoding hIL-17 was obtained by polymerase chain reaction (PCR) amplification from human CD4+ T-cell cDNA and inserted into the plasmid pRc/CMV to construct an expression vector for hIL-17. CHO cells were transduced with hIL-17 DNA-carrying cytomegalovirus (CMV)-based retroviral vectors. A clone with a high mRNA expression of hIL-17 (CHO/IL-17) was selected by Northem blotting. There was no significant difference in the in vitro growth of cells among parent CHO cells, vector-only transfected cells (CHO/neo) and CHO/IL-17 cells. A Matrigel invasion chamber assay, however, demonstrated significantly lower invasiveness by CHO/IL-17 cells than by either the parent CHO or the CHO/neo cells. There was no difference in the in vivo growth among the cells, when subcutaneously transplanted into nude mice. When injected into the tail vein, however, the number of metastatic nodules in the lungs of CHO/IL-17-injected mice was significantly smaller than that of CHO- or CHO/neo-injected mice. Furthermore, NK activity of spleen cells was significantly higher in nude mice transplanted with CHO/IL-17 cells than in mice transplanted with parent CHO or CHO/neo cells. In conclusion, the hIL-17-gene-transfected CHO cells showed a significantly lower metastatic potential to the lung by directly modulating the invasiveness and metastasis of CHO cells as well as by enhancing NK activity.
Animals↗
Induction of tumor-specific antitumor immunity after chemotherapy with cisplatin in mice bearing MOPC-104E plasmacytoma by modulation of MHC expression on tumor surface.
Chemotherapy sometimes results in induction of specific antitumor immunity. We investigated the mechanisms responsible for the induction of antitumor immunity in mice bearing MOPC-104E plasmacytoma after chemotherapy with cisplatin (CDDP), especially the effects of CDDP on the expression of MHC on the tumor surface. BALB/c mice were subcutaneously (s.c.) inoculated with MOPC-104E cells on day 0, then intravenously (i.v.) treated with CDDP at 3.6 mg/kg on day 7. The tumors disappeared completely on day 35 and the mice rejected a second challenge with MOPC-104E, but did not reject syngeneic Meth-A fibrosarcoma. The tumors did not regress, however, when MOPC-104E was s.c. transplanted in nude mice, or when anti-T-cell monoclonal antibodies were i.v. injected into BALB/c mice before CDDP treatment on day 6. To determine which of the mice or tumor were affected by CDDP, BALB/c mice were inoculated with CDDP-treated (12.5 micrograms/ml for 3 hours in vitro) MOPC-104E cells on day 0, 7 and 14. The potential to reject MOPC-104E was lower in mice immunized with ethanol-treated MOPC-104E cells than in those immunized with CDDP-treated cells. CDDP-treated or -untreated MOPC-104E cells ultrasonicated and fractionated into soluble and insoluble fractions by centrifuging, also induced antitumor immunity. Flow cytometry demonstrated that the expression of MHC-class-I antigens H-2Dd and H-2Kd was enhanced after CDDP-treatment, but that of class-II antigens I-Ad and I-Ed was not, suggesting that CDDP induced tumor-specific antitumor immunity by enhancing the expression of MHC-class-I antigens.
Animals↗
Plant polysaccharide PSK: cytostatic effects on growth and invasion; modulating effect on the expression of HLA and adhesion molecules on human gastric and colonic tumor cell surface.
PSK is a plant polysaccharide widely used for cancer immunotherapy in Japan and other Asian countries. It is considered that its antitumor effect is derived from its immunomodulating activity on the tumor-bearing host. The present study was designed to assess the direct action of PSK on in vitro proliferation and invasion of human KATO-3 gastric and Colo205 colonic cancer cell lines, and the expression of surface molecules such as HLA and adhesion molecules on these cells. The in vitro growth of KATO-3 cells was significantly inhibited by 100 micrograms/ml of PSK 48 hrs after culture initiation, and that of Colo205 was significantly inhibited by 10 and 100 micrograms/ml of PSK 24 hrs after culture initiation. The effect of PSK on the in vitro invasion of the tumor cells, assessed with a Matrigel invasion chamber, revealed that invasion of KATO-3 and Colo205 cells was inhibited by more than 10 micrograms/ml and more than 5 micrograms/ml of PSK, respectively. KATO-3 cells expressed HLA-ABC, HLA-A2/A28, HLA-DR very weakly, at almost baseline levels, but HLA-B27, B2-microglobulin and HLA-DQ were expressed at various levels. After treatment of KATO-3 cells with PSK, the expression of HLA-B27 and beta 2-microglobulin was significantly enhanced. Colo205 cells expressed all class-I antigens tested in this study at different levels, but class-II antigens at almost baseline levels. PSK also enhanced the expression of class-I antigens on Colo205 cells. ICAM-1 was expressed on KATO-3, but not on Colo205. The expression of ICAM-1 was enhanced to a greater extent by treatment with 10 micrograms/ml than with 100 micrograms/ml of PSK. Adenocarcinoma antigen AC-81 was strongly expressed on both cell lines, but PSK-treatment significantly enhanced its expression. These results suggested that enhancement of HLA class-I expression on tumor cells after PSK treatment may be one of the mechanisms responsible for the induction of anti-tumor immunity by PSK.
Antineoplastic Agents, Phytogenic↗
Antitumor activity of 5'-deoxy-5-fluorouridine in human digestive organ cancer xenografts and pyrimidine nucleoside phosphorylase activity in normal and neoplastic tissues from human digestive organs.
5'-Deoxy-5-fluorouridine (5'-DFUR) is believed to be metabolized to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). PyNPase activity is reported to be higher in neoplastic tissues than in normal tissues, and this has been proposed as an explanation for the selective cytotoxicity of 5'-DFUR against tumors. In the present study, PyNPase activity was measured in 95 neoplastic and normal specimens from human digestive organ tissues. In specimens from the esophagus, stomach, intestine and pancreas, PyNPase activity was higher in neoplastic tissues than in normal tissues. However, PyNPase activity in non-malignant liver tissues, especially cirrhotic liver tissues, was much higher than in the normal tissues of the other digestive organs. PyNPase activity in non-malignant liver tissues was a high as in primary liver tumors, and PyNPase activity in metastatic liver tumors was lower than in primary tumors and non-malignant cirrhotic tissues. The in vivo antitumor activities of oral 5'-DFUR and intravenous 5-FU were also assessed in 6 human digestive organ cancer xenograft lines transplanted subcutaneously in nude mice, and the relationship between the in vivo antitumor effects of 5'-DFUR and PyNPase activity in the tumors was assessed. However, there was no statistically significant correlation between them. Although the in vivo antitumor effect of intravenous 5-FU correlated significantly with the in vitro sensitivity of the tumors to 5-FU (assessed by DNA synthesis inhibition assay), the in vivo effects of 5'-DFUR did not correlate with the in vitro sensitivity to 5-FU. It is suggested that: (a) the liver may be the major site for metabolizing 5'-DFUR to 5-FU, and (b) measuring PyNPase activity in the tumor may not be a useful indicator for chemotherapy with 5'-DFUR.
Adenocarcinoma↗
The role of additional chemotherapy with oral UFT in intravenous combination chemotherapy with cisplatin and 5-fluorouracil for human gastric cancer xenograft lines of well- and poorly- differentiated adenocarcinomas transplanted in nude mice.
In order to assess the role of maintenance chemotherapy with the oral anticancer agent UFT, a mixture of uracil and futraful, in the intensive intravenous chemotherapy for gastric cancer, nude mice transplanted with human gastric cancer xenografts were treated with intravenous 5-fluorouracil (5-FU) and cisplatin (CDDP), alone or in combination, with or without the oral anticancer agent UFT. UFT was given at its maximal clinical dose of 10 mg/kg of body weight daily for 2 weeks, while 5-FU and/or CDDP was intravenously administered at the dose of 20 mg/kg and 1.8 mg/kg of body weight respectively once a week, alone or in combination, for two weeks. The results revealed that 5-FU or CDDP alone were ineffective for both GC-YN, a well differentiated adenocarcinoma line, and GC-SF, a poorly differentiated adenocarcinoma line; however, UFT was effective for GC-SF. In combinations, only the three-agent combination 5-FU + CDDP + UFT (FPU) was effective for GC-YN; however, all the two-agent combinations and FPU were effective for GC-SF. FPU significantly suppressed the growth of GC-YN much more than all the other treatment groups. In contrast, although all combinations as well as UFT alone were effective for GC-SF, there was no significant difference among these effective groups. Moreover, no side effects were noted in combined use of UFT. This study suggests that oral UFT as a maintenance treatment may be beneficial in the combination chemotherapy for human gastric cancer.
Adenocarcinoma↗
Relationships for recombinant interleukin-2-stimulated mixed lymphocyte tumor extract reaction between peripheral blood lymphocytes and regional node lymphocytes in gastric cancer patients.
To investigate the relationship between "systemic" antitumor immunity and "local" antitumor immunity with respect to the histopathological stage of gastric cancer, interleukin-2 stimulated mixed lymphocyte tumor extract reactions (ILS-MLTR) of peripheral blood lymphocytes (PBL) and regional node lymphocytes (RNL) were evaluated in 59 gastric cancer patients. ILS-MLTRs of both PBL and RNL decreased with the advance of cancer stage, but ILS-MLTRs of PBL were always lower than those of RNL. Positive correlations in MLTR between PBL and RNL were found in patients with depth of invasion to muscularis propria and serosa and peritoneal dissemination. Inverse correlations between PBL and RNL were noted in patients with stage IV and distant nodal involvement. These results suggest that variations in the anticancer immunities might be effectively managed by an immunotherapy which is designed according to the responsiveness in the immune parameter ILS-MLTR.
Cells, Cultured↗
Splenectomy abolishes antitumor effect of immunotherapy with streptococcal preparation, OK-432, on mouse liver tumors.
In the present study, we investigated the therapeutic effects of oral and subcutaneous administration of OK-432 prior to or following the transplantation of murine liver tumors. In addition, the effect of splenectomy on the antitumor activity of OK-432 was investigated. Mice which received OK-432 orally prior to tumor transplantation exhibited significantly lower tumor weight and significantly improved survival, when compared to the control mice. Prior subcutaneous injection of OK-432 did not show any antitumor activity. On the other hand, both oral and subcutaneous administration of OK-432, subsequent to tumor transplantation, led to a significant improvement of survival and a decrease in the number of lung metastases, although tumor weight was not affected. The anti-tumor effect of OK-432 required the presence of the spleen, since the survival of the mice with liver tumors was not improved by OK-432 if splenectomy and tumor transplantation were performed simultaneously. These results suggest that immunotherapy with OK-432 may beneficial in the treatment of liver tumors and that these effects are dependent on the presence of the spleen.
Animals↗
Relationship of in vivo antitumor activities of fluorinated pyrimidines to thymidylate synthase activity and intratumoral concentrations of 5-fluorouracil and uracil.
MOPC-104E plasmacytomas were subcutaneously transplanted into BALB/c mice and after 7 days the mice were administered different fluorinated pyrimidines at 4 times the clinical doses, 5-fluorouracil (5-FU, 15 mg/kg), tegafur (FT, 100 mg/kg) or UFT (FT, 20 mg/kg + uracil, 44.8 mg/kg) daily for 7 days. Tumor growth was most effectively inhibited in the UFT group. The % inhibition of tumor growth on day 14, while not correlating with the concentration of 5-FU in the tumor, negatively correlated with the concentration of uracil, which was lowest in the UFT group. The activity of thymidylate synthase (TS) was measured using a 5-fluoro-deoxyuridine monophosphate (FdUMP) binding assay. The total and free TS activities in the tumor negatively correlated with the % inhibition of tumor growth, and were lowest in the UFT group. However, the % inhibition of TS activity in the tumor, which was about 80% in all 3 groups, did not correlate with the tumor-inhibitory effect. These results suggest that uracil in the tumor may play an important role in the metabolism of fluorinated pyrimidines, and that exogeneously administered uracil may decrease the amounts of uracil and TS in the tumor, and subsequently cause 5-FU accumulation.
Animals↗
In vivo inhibitory effect of anticancer agents on human pancreatic cancer xenografts transplanted in nude mice.
Pancreatic cancer is one of the neoplasms resistant to chemotherapy. In the present study human pancreatic cancer xenografts (3 adenocarcinomas and 1 cystoadenocarcinoma) were subcutaneously transplanted in nude mice and after the tumors grew to 100-300 mm3, the mice were intraperitoneally administered with mitomycin C (MMC), adriamycin (ADR), 5-fluorouracil (5-FU), carboquone (CQ), cisplatinum (CDDP), nimustine chloride (ACNU) or DWA2114R at 1/3 LD50 on days 0.4, and 8. The tumor sizes on day 12 were compared with those on day 0. MMC and CQ significantly inhibited the tumor growth of 3 lines, and ACNU, CDDP and ADR inhibited the growth of 1 line. Further, 5-FU, futrafur, carmofur, UFT and L-phenylalanine mustard (L-PAM) were orally administered to mice into which 1 adenocarcinoma line had been transplanted. While none of fluoropyrimidines inhibited tumor growth, L-PAM at 4 mg/kg significantly inhibited growth, although it was accompanied by severe body weight loss. In the present study several agents significantly inhibited tumor growth, but none of them could induce the regression of the tumor when used singly. These results suggest that CQ, ACNU, CDDP and L-PAM may be applied to the chemotherapy of pancreatic cancer. However, the effect of a single agent is restricted and the development of new combination treatments is urgently required.
Adenocarcinoma↗
In vitro and in vivo antineoplastic activity of a new platinum antineoplastic agent, (R)-(-)-1,1-cyclobutanedicarboxylate (2-aminomethylpyrrolidine)-platinum (II) (DWA2114R) on freshly separated human tumor cells and human tumor xenografts transplanted in nude mice--a comparison with cis-diammine-dichloroplatinum (CDDP).
The in vitro antimetabolic effect of a newly synthesized platinum antineoplastic agent, DWA2114R, on 72 fresh human tumors was compared with that of cis-platinum (CDDP). DWA2114R is reported to have a lower nephrotoxicity than CDDP, but is as strong an inhibitor of DNA synthesis as CDDP. In vitro IC50 was assessed in 10 tumors; the IC50 of DWA2114R ranged between 9.2 and 107 microM (mean +/- S.D., 45.9 +/- 36.6) and that of CDDP ranged between 0.9 and 40 microM (18.3 +/- 15.1). DWA2114R had an antitumor spectrum similar to that of CDDP. Primary esophageal and pancreatic cancers were sensitive to DWA2114R, and cells separated from malignant effusion or metastatic lymph nodes were more sensitive than those from primary lesions. Nude mice were transplanted with 3 kinds of human tumor xenografts (esophageal, pancreatic and bile duct cancer lines), and were then treated with CDDP or DWA2114R at 4 times the clinical doses. CDDP significantly inhibited the growth of all the 3 lines, and DWA2114R inhibited the growth of 2 of the lines. The effect of DWA2114R on body weight was smaller than that of CDDP. These results suggest that DWA2114R may be less potent than CDDP but may be useful as a new platinum antineoplastic agent with lower grade of side effects than CDDP.
Adenocarcinoma↗
Augmentation of cytotoxicity of lymphokine activated killer cells on ovarian tumor cells by various biological response modifiers.
The effect of combining lymphokine activated killer (LAK) cells with either recombinant interleukin-2 (rlL-2), recombinant interferon-alpha (rIFN-alpha), recombinant tumor necrosis factor (rTNF) or streptococcal preparation OK-432 were assessed, using Raji, 2 kinds of cultured ovarian lines (PA-1 and SKOV-3), and 7 fresh ovarian tumor lines. LAK cells were generated by culturing peripheral blood lymphocytes (PBL) with rIL-2 for 3-5 days. The simultaneous combination of LAK cells with rIFN alpha or OK-432 augmented the cytotoxicity of LAK cells. The susceptibility of tumor cells to LAK cells also increased after the pretreatment of tumor cells with OK-432. These results suggest that the simultaneous injection of LAK cells with rIFN-alpha or OK-432 and the intralesional injection of OK-432 prior to the adoptive transfer of LAK cells may be a beneficial combination treatment for LAK treatment.
Biological Products↗