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Biomedical subjects

Y Otani

Publications and source records attributed to Y Otani.

214 records · Page 12Linked to original sources
PubMedDate not supplied

Palatal ruga anomaly induced by all-trans-retinoic acid in the Crj:SD rat: possible warning sign of teratogenicity.

We have reported that the critical period for cleft palate formation by all-trans-retinoic acid (RA) is on gestation day 14 in rats, and classified abnormal patterns of palatal rugae into minor variations and anomalous patterns. In this study, we examined the dose-response relationship for cleft palate and an anomalous pattern of palatal rugae formation and discussed the toxicologic significance of the palatal ruga anomaly as an indicator of teratogenicity. The ED(50) values for cleft palate and anomalous pattern were calculated to be 43.6 and 4.95 mg/kg, respectively. The results clearly show that anomalous rugal patterns occur in the fetuses from litters receiving RA at a lower dose than cleft palate induction; the anomalous ruga pattern is thus more sensitive than cleft palate induction. The anomalies of palatal rugae could be taken as a warning sign or an indicator of teratogenicity of a drug.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Gastric microcirculatory disturbance and behaviour of leucocytes after thermal injury: intravital observation of arteriovenous shunting channels in the gastric submucosal layer.

In order to investigate the pathogenesis of acute gastric mucosal lesion after thermal injury, microcirculatory disturbance was assessed and observation of the behaviour of leucocytes was performed. Gastric blood flow decreased at 15 min post-thermal injury, and partially improved at 2 h; however, it decreased again at 5 h post-thermal injury. Mucosal microcirculatory disturbance was observed by using vascular labelling with monastral blue B. Deposits of monastral blue B were observed centring mainly on collecting venules but were also observed in the capillaries. Submucosal microcirculatory disturbance was observed through an intravital microscope. The irregularity of the wall and segmental constriction in the venules and presence of an arteriovenous shunting channel was observed in the submucosal layer at 5 h post-thermal injury. The percentage of rolling or sticking leucocytes that passed the confluence of a prevenule and a venule were significantly increased at 5 h after thermal injury. The present study revealed depression of gastric blood flow, mucosal and submucosal microcirculatory disturbance, and a significant increase of rolling and sticking leucocytes in the peripheral part of venules after thermal injury. Leucocyte-endothelial interactions may occur under such conditions and this interaction may play an important role in inducing the microcirculatory disturbance that results in an acute gastric mucosal lesion after thermal injury. The present study also demonstrated the possibility of intravital study of gastric submucosal arteriovenous shunting channels.

Animals↗
PubMedDate not supplied

Interferon gamma increases the antitumor activity of mitomycin C against human colon cancer cells in vitro and in vivo.

A combined antitumor activity of mitomycin C (MMC) and interferon gamma-1a (IFN-gamma) was evaluated to be synergistic by the 3-(4, 5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide assay and human tumor xenografts/severe combined immunodeficient (SCID) mouse system using colon cancer cell lines. The experimental metastasis of WiDr cells in SCID mouse was inhibited by MMC and IFN-gamma with their synergism. Intracellular uptake of MMC in WiDr cells in vitro was significantly increased by IFN-gamma, suggesting the mode of synergism of these agents. This model may also partly explain the antitumor activity of combined MMC, 5-fluorouracil and interleukin-2 treatment on hepatic metastasis of colon cancer.

Animals↗
PubMedDate not supplied

Thymidine phosphorylase expression and effect of doxifluridine: a phase II study.

Doxifluridine (5'-DFUR), an active intermediate metabolite of capecitabine, is converted to 5-fluorouracil by thymidine phosphorylase (TP). We used immunohistochemical staining to investigate the relation between TP expression and 5'-DFUR effects in 40 patients with advanced/recurrent lung metastases from colorectal cancer. Cox regression analysis suggested that TP-positive cancer cells (risk ratio 3.72), were independent factors in survival whereas factors in progression-free survival were TP-positive cancer cells (2.93), and TP-positive stromal cells (0.24). It is suggested that TP expression in cancer cells and in stromal cells are opposite prognostic factors in patients treated with 5'-DFUR.

Adult↗
PubMedDate not supplied

Combined antitumour activity of mitomycin C, 5-fluorouracil and interleukin-2 against human colon cancer cells.

Combined treatment of interleukin-2 (IL-2), 5-fluorouracil (5-FU) and mitomycin C (MMC) is reported to be effective against hepatic metastasis of colon carcinoma. To clarify this modality, we investigated lymphokine activated killer (LAK) activity of human peripheral lymphocytes on colon cancer cell lines by 51Cr release assay. LAK activity against Colo 205 cells by untreated lymphocytes was 12%, which increased to 25% upon the addition of 5-FU, but remained unchanged upon the addition of MMC. The combined antitumour activity of MMC or 5-FU with or without LAK-supernatant was evaluated by MTT assay; antitumour activity of MMC was increased by the addition of LAK-supernatant. The concentration of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) was increased in LAK-supernatant, and the antitumour activity of combined IFN-gamma and MMC was synergistic. The mechanism of this therapy seemed to be associated with both increased LAK activity by 5-FU and increased antitumour activity of MMC with IFN-gamma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Chemosensitivity test is useful in evaluating the appropriate adjuvant cancer chemotherapy for stage III non-scirrhous and scirrhous gastric cancers.

A total of 183 cases with gastric cancer was retrospectively analyzed in terms of their chemosensitivity as determined by the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay and their survival rates after surgery. After the patients were stratified into scirrhous or non-scirrhous carcinoma groups, they were tested for stage III or IV gastric cancer. In these four cohorts, the patients were categorized into sensitive and insensitive groups determined by the MTT assay. The sensitive group was treated with at least one drug that had been shown to be effective in the MTT assay, and the insensitive group was given a drug that had been shown to be ineffective in the MTT assay. In stage III gastric cancer, the sensitive group showed a favorable survival compared to the insensitive group in scirrhous and non-scirrhous carcinoma, while this difference was diminished in stage IV gastric cancer. There were no survival benefits in the sensitive group in stage III gastric cancer, when they were not treated with adjuvant cancer chemotherapy. These results suggested that MTT assay would be useful in evaluating the appropriate adjuvant cancer chemotherapy for stage III scirrhous and non-scirrhous gastric cancer.

Adenocarcinoma, Scirrhous↗
PubMedDate not supplied

Chemosensitivity testing of primary tumor cells from gastric cancer patients with liver metastasis can identify effective antitumor drugs.

The liver metastasis of gastric carcinoma is resistant to conventionally available treatment. Twenty patients with liver metastasis of gastric cancer were treated by arterial drug infusion using a reservoir and seven cases were treated with systemic chemotherapy. The resected primary gastric cancer specimen was used for chemosensitivity assay with 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) endpoint, and the patients were treated without reference to the results of the chemosensitivity assay. The mean survival period was assessed according to the histology of the primary lesion, the grade of liver metastasis and, the presence of peritoneal dissemination. No significant differences were observed in the primary tumor histology and grade of liver metastasis, but the survival period of the patients with liver metastasis and peritoneal dissemination was significantly shorter than that of the patients without peritoneal dissemination. Nine patients were treated with drugs that were effective in the chemosensitivity assay, and their responses included two complete responses and two partial responses; these patients showed a significantly prolonged survival period compared with patients treated with drugs that were not effective in the assay. The chemosensitivity assay is useful for evaluating the effectiveness of antitumor agents against liver metastasis of gastric cancer.

Adult↗
PubMedDate not supplied

Thymidylate synthetase and dihydropyrimidine dehydrogenase levels in gastric cancer.

The measurement of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) enzymatic activities and mRNA levels in tumors may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in this study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD mRNA levels. We also measured TS and DPD enzymatic activities and mRNA levels in surgically resected gastric cancer samples, as well as in adjacent normal gastric mucosa. TS and DPD activities were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-PCR (RT-PCR) co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. In resected tumor specimens, TS and DPD activities ranged from 7.1 to 176.6 fmol/mg protein and from 3.6 to 99.8 pmol/min/mg protein, respectively, while TS and DPD mRNA levels ranged from 0.50 to 21.12 and from 0.014 to 7:22, respectively. There were no significant correlations between TS/DPD levels and other clinicopathological factors, except for low DPD mRNA levels in undifferentiated carcinoma. Both TS activity and mRNA levels were significantly higher in tumor tissues compared to normal adjacent mucosa. In contrast, there was no significant difference between tumoral and non-tumoral DPD activity, although tumor tissue showed significantly lower DPD mRNA levels than non-tumoral tissue. High tumoral TS mRNA levels in preoperative biopsy specimens from patients with stage III/IV was associated with poor survival outcome after surgery compared with patients with low tumoral TS mRNA levels. In contrast, DPD levels had no influence on prognosis. We conclude that high tumoral TS levels and low tumoral DPD mRNA may indicate the selective cytotoxicity of 5-FU on gastric cancer, and that tumoral TS mRNA levels may be a prognostic factor for patients with stage III/IV gastric cancer.

Aged↗
PubMedDate not supplied

Docetaxel enhances the cytotoxicity of tetrahydropyranyladriamycin in a sequence-dependent manner.

BACKGROUND: Taxanes and anthracyclines are active against breast cancer. In this study we investigated the combined antitumor activity of these drugs, with particular regard to sequence-dependency. MATERIALS AND METHODS: The combined antitumor activity of docetaxel and tetrahydropyranyladriamycin (THP) against two human breast cancer xenografts was assessed using an in vitro histoculture drug-response assay. The sequence-dependency of the combined cytotoxicity was evaluated by isobologram. RESULTS: A synergistic antitumor activity of combined docetaxel + THP was exhibited against the R-27 xenograft when docetaxel was given first or simultaneously with THP. However, this synergism was diminished when THP was used before docetaxel. While an additive effect of combined docetaxel + THP was observed against MX-1 xenograft when docetaxel was given first or simultaneously with THP, this effect was not marked using the THP/docetaxel sequence. CONCLUSION: Docetaxel increased the antitumor activity of THP, but only when administered before or simultaneously with THP.

Adult↗
PubMedDate not supplied

Interferons alpha-2a and beta increase the antitumor activity, detected by MTT assay, of 5-fluorouracil against experimental and clinical human gastrointestinal carcinomas.

In order to investigate the combined antitumor activity of 5-fluorouracil (5-FU), and recombinant human interferon alpha 2a (IFN alpha) or human fibroblastoid interferon beta (IFN beta), the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was carried out using a cultured human colon cancer cell line (C-1) and fresh surgical specimens of gastric and colon carcinomas. IFNs did not show positive antitumor activity against C-1 cells, whereas 5-FU showed time- and concentration-dependent antitumor activity against C-1 cells. Furthermore, the antitumor activity of 5-FU on C-1 cells was augmented by IFN alpha or beta. When 5-FU (50 micrograms/ml) with IFN alpha (50 IU/ml). or IFN beta (50 IU/ml) was applied for the MTT assay with 48 hours incubation of fresh surgical specimens of gastric and colon carcinomas, the inhibition rates increased by 10% in 9 of 21 gastric specimens and in 18 of 36 colon carcinomas for IFN alpha (47.4% or 27/57), and in 8 of 15 gastric specimens and in 15 of 28 colon carcinomas for IFN beta (53.5% or 23/43). These results suggest that the chemosensitivity to 5-FU of human gastric and colon carcinomas is increased in the presence of IFNs, without involvement of the host-mediated immune system, and that this combined effect can be predicted by the MTT assay in vitro.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

MKT-077, localized lipophilic cation: antitumor activity against human tumor xenografts serially transplanted into nude mice.

BACKGROUND: In in vitro experiments, the localized lipophilic cation, MKT-077, demonstrated time- and concentration-dependent antitumor activity. In the present experiment, the in vivo antitumor activity of MKT-077 was evaluated using human tumor xenografts serially transplanted into nude mice. MATERIALS AND METHODS: The antitumor efficacy of MKT-077 against five xenografts inoculated subcutaneously into nude mice was studied. Treatment with MKT-077 was initiated when the tumors started exponential growth. The antitumor activity of MKT-077 was assessed by a) the lowest value of the relative mean tumor weight of the treated:control tumors (T/CRW), where relative weight (RW) represented the change from baseline weight; and by b) the unadjusted weight of treated tumors at the end of the experiment. RESULTS: When MKT-077 was administered continuously using the Osmotic Micropump, antitumor activity was positively correlated with exposure time and drug concentration from 7.5 to 40 mg/kg/day. The maximum tolerated dose was 20 mg/kg/day for 7 days. Co-4 (human colon cancer), St-4 (human gastric cancer), and CRL1420 (human pancreatic cancer) were evaluated as sensitive to MKT-077 in tested 5 strains. CONCLUSION: The antitumor activity of MKT-077 was confirmed using human tumor xenografts in nude mice.

Animals↗
PubMedDate not supplied

Further evidence for the value of the chemosensitivity test in deciding appropriate chemotherapy for advanced gastric cancer.

BACKGROUND: The chemosensitivity test using the MTT endpoint is useful in predicting chemosensitivity. PATIENTS AND METHODS: One hundred twenty-eight patients with advanced gastric cancer were enrolled in the study, which mitomycin C (MMC), doxorubicin (DXR), 5-fluorouracil (5-FU), and cisplatin (DDP) were used. RESULTS: The corresponding efficacy rates were 12.5% for MMC, 6.3% for DXR, 5.4% for 5-FU and 13.4% for DDP. The overall predictive accuracy was 78% in the patients with measurable lesions. Among the patients without measurable lesions, 21 were treated with a curative operation, and 33 with a non-curative operation. In those patients undergoing curative surgery, the "adapted" group detected by MTT assay survived longer than "non-adapted" cases (p < 0.05). CONCLUSIONS: The present study provides further evidence that the chemosensitivity test may be useful for evaluating appropriate chemotherapy for advanced gastric cancer.

Aged↗
PubMedDate not supplied

Antitumor activity of murine monoclonal antibody NCC-ST-421 on human cancer cells by inducing apoptosis.

BACKGROUND: The murine monoclonal antibody NCC-ST-421 (ST-421) recognizes dimeric Le(a) antigen expressed on gastrointestinal cancer cells. MATERIALS AND METHODS: Direct antitumour activity of ST-421 was evaluated using dimeric Le(a) positive cell lines Colo 205, Colo 201, HT-29 and WiDr; and negative cell lines MX-1 and K562. RESULTS: While time- and concentration-dependent antitumour activity was observed against Colo 205 and Colo 201, no antitumour activity was detected against the other cell lines tested in an in vitro cytotoxicity assay. When ST-421 was administered intraperitoneally daily for 2 weeks to severe combined immunodeficient (SCID) mice transplanted with tumour xenografts, inhibition of tumour growth was observed against Colo 205, and to a lesser extent HT-29 and WiDr. Anti-asialo GM1 antibody did not block this antitumour activity, suggesting ST-421 has a direct cytotoxic effect. The degree of antitumour activity of ST-421 dependent on the grade of Le(a)-expression as detected by immunohistochemical staining. CONCLUSIONS: Flow cytometric and immunohistochemical analysis suggests the induction of apoptosis may play a key role in the direct antitumour activity of ST-421 on Colo 205 cells.

Animals↗
PubMedDate not supplied

Management of primary gastric lymphomas from a surgeon's viewpoint.

Primary gastric lymphoma is a relatively uncommon disease and controversy still exists over its management. In order to assess prognostic factors of lymphomas, we carried out a retrospective study of 28 surgically treated gastric lymphoma patients. The overall survival rate for all the patients in the study was 33% at 10 years. On univariate analysis, lymph node metastasis and depth of tumor infiltration proved to be a significant prognostic factor while size and location of tumor, sex, and method of resection was not. From our results we believe that gastric lymphoma can be regarded as a localized disease in the early stages and a curative resection can be attained when aggressive surgery is possible.

Aged↗