Biomedical subjects

T Tsunoda

Publications and source records attributed to T Tsunoda.

322 records · Page 18Linked to original sources

PubMedDate not supplied

P-glycoprotein expression and chemosensitivity in highly purified fresh human gastrointestinal cancer cells.

BACKGROUND/AIMS: Colorectal cancer is one of the tumors most refractory to treatment by chemotherapy. One of the major problems associated with cancer chemotherapy is drug-resistance of tumor cells, and resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein. We have tried to prove the correlation between P-glycoprotein expression and DOX-sensitivity in highly purified fresh human colorectal cancer and, moreover, to prove the differentiation of P-glycoprotein expression between the different kinds of cancers, including gastric cancer. METHODOLOGY: The present study was designed to quantify P-glycoprotein expression by flow cytometry, and DOX-sensitivity by MTT assay in highly purified fresh human tumor cells obtained from 29 cancer patients including 13 colorectal cancers and 16 gastric cancers. RESULTS: DOX-sensitivity decreased in proportion to P-glycoprotein expression in colorectal cancer. P-glycoprotein expression in colorectal cancer was higher than that in gastric cancer. Particularly, P-glycoprotein expression in colorectal cancer in the DOX low-sensitivity group was higher than in the DOX high-sensitivity group. CONCLUSIONS: The chemotherapeutic management of patients with colorectal cancer might be more effective if we can circumvent the effect of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Multidisciplinary treatment for gastric cancer patients by chemoimmunotherapy.

BACKGROUND/AIMS: Gastric cancer is a virulent disease with a poor prognosis despite multidisciplinary treatment. The present study was designed to clarify the clinical effects of chemoimmunotherapy for patients with advanced gastric cancer. METHODOLOGY: The enrolled gastric cancer patients had distant metastases including liver (n = 2) and peritoneal dissemination (n = 21). The patients had received the chemotherapy according to the results of chemosensitivity test and adoptive immunotherapy by activated killer cells. RESULTS: There were no severe toxicities, except fever and mild myelo-suppression. Four patients had complete response (17.4%) and 10 patients had partial response (43.5%). The performance status was improved in responders (p < 0.01, from 2.6 +/- 0.5 to 1.4 +/- 0.7); however, this was not changed in non-responders (from 2.2 +/- 0.9 to 2.0 +/- 1.2). The survival of responders was longer than that of non-responders (p < 0.05, 198 +/- 69 days vs. 104 +/- 68 days). CONCLUSIONS: It was clarified that responders by chemoimmunotherapy had a good quality of life and longer survival.

Aged↗

PubMedDate not supplied

Clinical evaluation of hepatic arterial infusion of low dose-CDDP and 5-FU with hyperthermotherapy: a preliminary study for liver metastases from esophageal and gastric cancer.

BACKGROUND/AIMS: The prognosis for gastric and esophageal cancer patients with liver metastases remains very poor. In most cases, liver metastasis is unresectable because of its number, size and location and therefore, other approaches need to be considered. METHODOLOGY: In this study we examined 4 patients. We showed the therapeutic benefits of employing hepatic arterial infusion of low-dose CDDP and 5-FU combined with hyperthermia for the treatment of liver metastases of gastric and esophageal cancer. RESULTS: All patients showed partial response, and bone marrow toxicities and gastrointestinal toxicities were extremely slight while liver toxicities were not observed at all. Moreover, 3 of the patients excluding patient 3 who had metastatic lesions other than liver metastases have still been alive for more than 17 months (17-28 months) maintaining a good quality of life. CONCLUSIONS: Therefore, it is suggested that the merits of both low dose-FP and hepatic arterial infusion chemotherapy contribute to ideal clinical effects, and that hyperthermotherapy could enhance clinical responses without potentiating any toxicities. However, this is just a preliminary study, and therefore, a prospective randomized control study is necessary to evaluate the efficiency of this therapy.

Aged↗

PubMedDate not supplied

Neutrophil functions and cytokine production in patients with gastric cancer.

BACKGROUND/AIMS: One of the most important factors in the prevention of postoperative infection is the patient's own capacity to protect against infection. Neutrophils play a major role in this protection through phagocytosis and superoxide generation. Inflammatory cytokines are suitable for estimating the degree of surgical stress. The present study was designed to elucidate whether neutrophil functions are impaired in gastric cancer patients, and are related with cytokine production after surgery. METHODOLOGY: Phagocytosis and superoxide generation by neutrophils was studied in 84 patients with gastric cancer by flow cytometry. IL-6, IL-8 and tumor necrosis factor alpha were studied in 18 patients with gastric cancer by enzyme-linked immunosolubent assay. RESULTS: In gastric cancer patients phagocytosis was not impaired, whereas superoxide generation was lower than benign diseases and it was inhibited relative to the clinical stage. Moreover, superoxide generation was correlated with the nutritional parameters and was more suppressed in 7 patients who suffered from postoperative infection than in 40 patients whose postoperative course were uneventful. The fluctuation of superoxide generation correlated well with the serum cytokine levels in the postoperative course and its correlation was clarified in vitro. Nine patients with gastric cancer received intravenous hyperalimentation, and their superoxide generation was increased. CONCLUSIONS: Superoxide generation by neutrophils was suppressed in gastric cancer patients and it is suggested that nutritional support prevents postoperative infection via the augmentation of superoxide generation.

Aged↗

PubMedDate not supplied

In vitro antitumor effect of topoisomerase-I inhibitor, CPT-11, on freshly isolated human gastric and colorectal cancer.

CPT-11 is a comptothecin analogue which has shown a broad spectrum of strong antitumor effect against various cancers, including gastroenterological malignancies. In the present study, the antitumor effect of CPT-11 was determined by MTT assay for freshly isolated human gastric and colorectal cancer cells, especially highly purified tumor cells. Twenty-three patients with gastric cancer, and 32 patients with colorectal cancer were enrolled in this study. Three gastric and 3 colonic cancer cell lines were used to study the antitumor effect of CPT-11, and freshly isolated cancer cells from 3 patients with gastric cancer were investigated. The in vitro antitumor effect was tested by MTT assay, and showed % inhibition rate. CPT-11 and SN-38 showed the antitumor effect as a dose dependent matter for human gastric and colorectal tumor cells in vitro. From the results of chemosensitivity for freshly isolated gastric and colorectal tumor cells, antitumor effect of SN-38 was as strong as other conventional anticancer agents. It was demonstrated that the MTT assay was appropriate for the analysis of the antitumor effects of CPT-11 and SN-38, and that CPT-11 may be a worthwhile choice as an anticancer agent against gastric and colorectal cancer.

Antineoplastic Agents↗

PubMedDate not supplied

Upregulated expression of angiogenesis genes and down regulation of cell cycle genes in human colorectal cancer tissue determined by cDNA macroarray.

The differential expression of hundreds of tightly, transcriptionally controlled genes in isolated human colorectal cancer and respective normal mucosa from two patients was analyzed by the cDNA macroarray technique. mRNA prepared from the colorectal cancer tumors was compared with 588 genes spotted onto the filter. Case A showed down-regulation of the expression of cell-cycle-related genes including cyclins, cyclin-dependent kinase (CDK) 2, and CDK-activating kinase, as compared with normal mucosa from the same patient. The tumors showed up-regulation of expression of angiogenesis-related genes such as type II cytoskeletal 8 keratin, metalloproteinase subtypes, VEGF, and bFGF, to over 5-fold the levels in normal mucosa. Thus, colorectal carcinoma tissues are characterized by the upregulation of molecules related with angiogenesis. These results suggest that angiogenesis-related molecules are suitable candidates for target-based therapies for colorectal cancer patients. In case B, the largest difference in expression between the tumor and mucosal tissues was observed in the MMP-1 gene. In contrast to the first case, there was no increase in expression of angiogenesis-related molecules or decrease in expression of cell-cycle-regulatory molecules. The expression profile was quite different between these two patients. This approach may eventually provide a mean of selecting target-based drugs in individual colon cancer patients.

Adult↗

PubMedDate not supplied

In vitro antitumor activity of TAS-103 against freshly-isolated human colorectal cancer.

DNA topoisomerases (Topo) are enzymes that relieve the secondary twist on the DNA strand in the process of DNA synthesis and transcription; therefore they are unique targeting molecules for the chemotherapy of colorectal cancer. TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-in-deno [2,1-c]quinolin-7-one dihydrochloride, MW; 406.31), a novel quinoline derivative, has recently been established as a Topo I and Topo II inhibitor. The aim of the present study was to investigate the antitumor activity of TAS-103 by the MTT assay in human highly-purified and freshly-isolated colorectal cancer cells. To our knowledge, this is the first data concerning the antitumor activity of TAS-103 in highly-purified and isolated human colorectal cancer cells. TAS-103 showed the strongest antitumor activity among the conventional anticancer agents for colorectal cancer (p<0.05). The combination with CDDP augmented the antitumor activity of TAS-103 (p<0.05), indicating that CDDP is one of the most potent candidates to be used in combination with TAS-103. To predict the clinical effect of TAS-103, the expressions of Topo I and Topo II were measured by quantitative PCR. However, a correlation between the expression of Topo and the antitumor activity of TAS-103 was not established. In conclusion, according to this data, TAS-103 may be useful in the chemotherapy of colorectal cancer.

Aminoquinolines↗

PubMedDate not supplied

A subepidermal blistering dermatosis associated with coexistent IgG and IgA anti-dermal basement membrane zone antibodies; demonstration of IgG antibodies reactive against a 200-kDa dermal antigen.

We report a 66-year-old woman presenting with an annular erythematous and bullous eruption. Her clinical and histological findings were similar to those of linear IgA bullous dermatosis or dermatitis herpetiformis. Direct immunofluorescence revealed linear deposition of IgA, IgG and C3 along the basement membrane zone (BMZ). Indirect immunofluorescence detected IgG and IgA antibodies against the BMZ. Salt-split skin technique demonstrated that IgG antibodies bound exclusively to the dermal side, while IgA antibodies bound not only to the dermal side, but also to the epidermal side with relatively weak intensity. On immunoblot analysis, the patient's IgG antibodies exclusively reacted with a band of 200-kDa, while the antigenic target of IgA antibodies was not identified. The present case is thought to be a unique bullous dermatosis mediated by both the IgG antibodies to a novel 200-kDa antigen and IgA antibodies against undetermined antigens.

Aged↗

PubMedDate not supplied

Non-T cell disturbance causes the suppression of the autologous mixed lymphocyte reaction in patients with gastric carcinoma.

We investigated the accessory function of non-T cells to autoreactive T cells in autologous mixed lymphocyte reaction (AMLR) and clarified the cause of the suppression of autoreactivity in patients with gastric carcinoma. The response of T cells in the AMLR in gastric cancer patients was significantly suppressed compared with that in controls. In patients in whom the AMLR of the spleen was suppressed more than that of the peripheral blood, the degree of stimulation of non-T cells from the spleen was remarkably suppressed, on the other hand, in patients in whom AMLR of the peripheral blood was suppressed more than the spleen, the degree of stimulation from the peripheral blood was remarkably suppressed. The expression of HLA-DR antigens on non-T cells of gastric cancer patients was lower than that of controls. AMLR was considerably decreased in controls by the treatment non-T cells with anti-HLA-DR MoAb, but not in cancer patients. Treatment of non-T cells from the spleen of gastric cancer patients with IFN-gamma remarkably improved T cell proliferation in the AMLR. IFN-gamma also enhanced the expression of HLA-DR antigens on non-T cells. The disturbance of non-T cells was not biased to a specific population. These disturbances of non-T cells suppressed the AMLR independently of stage status. Therefore, the immunological abnormality of non-T cells manifested by reduced accessory function to autoreactive T cells may cause impaired immunological surveillance against tumors and permit cancer cell growth.

Antibodies, Monoclonal↗

PubMedDate not supplied

Polysaccharide preparation PSK augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes in vitro.

We have investigated whether or not polysaccharide preparation PSK directly augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes (TILs). TILs were separated from 10 patients with gastrointestinal cancer (5 gastric cancers, 3 colon cancers and 2 pancreatic cancers). TILs were cultured with IL-2 and PSK for 7 days. The DNA synthesis of TILs was augmented by incubation with 100 micrograms/ml of PSK, which was similar to serum level with oral administration of PSK in cancer patients. The effect of PSK in DNA synthesis was also found by elimination of non-T cells. Furthermore, we established TIL clones and examined the effect of PSK on TILs clones. The DNA synthesis was augmented by PSK in CD4 positive and CD8 positive TIL clones without non-T cells, suggesting that PSK acts directly on TILs. We examined the cytotoxic activities of TILs by the 4-h and 16-h 51Cr release assay. PSK did not affect the cytotoxic activity of TILs against autologous tumor cells and KATO-III cells in the 4h 51Cr release assay, whereas PSK induced high lysability of TILs against autologous tumor cells in the 16-h 51Cr release assay. We studied the ability of PSK to induce cytokines from TILs using a double chamber plate. The DNA synthesis of tumor cells was more suppressed by the mixed-tumor cell culture supernatants of TILs cultured with PSK, compared to that of TILs cultured without PSK. It is suggesting that PSK induced long term killing activity of TILs by induction of cytotoxic cytokines. Thus, PSK augmented the proliferative response of TILs without interaction of T cells and non-T cells and induced cytotoxic cytokines of TILs.

Cell Division↗

PubMedDate not supplied

In vitro augmentation of cytotoxic activity of peripheral blood lymphocytes and spleen cells of cancer patients by ubenimex.

Ubenimex is used for the immunotherapy of malignant diseases as a biological response modifier (BRM) and shows beneficial effects as an adjuvant treatment. In the present study, the in vitro effects of ubenimex on the cytotoxic activity of peripheral blood lymphocytes (PBL) and spleen cells of cancer patients and the mechanism of killer cell activation were investigated. Cytotoxic activity against K562, KATO-III and autologous tumor cells was augmented by in vitro sensitization with ubenimex (p < 0.05). The optimal concentration of ubenimex for induction of cytotoxic activity was 1 micrograms/ml, similar to serum levels after clinical oral administration. The major population of killer cells activated by ubenimex recognizing K562 was CD16+, and those recognizing KATO-III were mainly CDA+ or CD8(5) cels and CD16+ NK cells, while CDA5 or CD8+T cells comprised the majority of killer cells which showed autologous tumor-killing activity. Augmentation of the cytotoxic activity of mononuclear cells by ubenimex was blocked by both anti-IL-1 beta Ab and anti-IL-2 AB. However, the expression of IL-2 receptor (p55, p75) on effector cells was not altered. Ubenimex augmented not only NK activity but also autologous tumor killing activity of PBL and spleen cells via macrophage activation. These activities of ubenimex may be clinically beneficial as an adjuvant treatment.

Adjuvants, Immunologic↗

PubMedDate not supplied

Ubenimex treatment enhances the susceptibility of gastric cancer cell lines to lymphokine-activated killer cells.

We investigated the direct effects of ubenimex on the modification of gastric carcinoma cell lines' susceptibility to killer cells, and the mechanism of its action. The susceptibility of both MKN-45 cells and KATO-III cells to LAK cells was enhanced by treatment with ubenimex for 48 h (p < 0.05), and the optimal concentration for this effect was 10 micrograms/ml. The susceptibility of ubenimex treated KATO-III cells to CD3+ LAK cells, especially to those also expressing CD8, was enhanced. DNA synthesis of tumor cells was not impaired by treatment with ubenimex at all concentrations tested. The binding rate of LAK cells and ubenimex-treated KATO-III cells was similar to that between LAK cells and untreated KATO-III cells. Moreover, no alterations in the expression of any antigen related to mononuclear cell-binding to tumor cells were induced by ubenimex. Lysis or the inhibition of DNA synthesis of tumor cells by LAK cell supernatant was enhanced by ubenimex. These results suggested that the mechanism responsible for the augmentation of tumor cell susceptibility by ubenimex may be a result of the alteration of their sensitivity to some Iytic factors released by LAK cells. Thus ubenimex shows not only an indirect host-mediated anti-tumor activity but also a direct effect on tumor cells, modifying their susceptibility to killer cells, and this may explain why ubenimex shows beneficial clinical effects as an adjuvant treatment.

Adjuvants, Immunologic↗

PubMedDate not supplied

Augmentation of lymphokine-activated killer cell activity by lentinan.

Lymphokine-activated killer (LAK) activity stimulated by interleukin 2 (IL-2) and/or lentinan was examined in the peripheral blood of 9 healthy subjects and 7 cancer patients. After 4 and 8 days culture, LAK killer activity stimulated by IL-2 and lentinan against autologous tumor and K562 cells was greater than that stimulated by IL-2 alone. The optimal concentration of lentinan for the generation of killer cells ranged from 25-500 ng/ml, a level which can be achieved in vivo by the administration of clinical doses of this agent. The expression of CD25 antigen, the alpha chain of the IL-2 receptor on the activated killer cells was increased by lentinan. Thus it was shown that LAK cells stimulated with IL-2 plus lentinan had strong cytotoxicity and might be useful as effector cells for adoptive immunotherapy.

Cytotoxicity, Immunologic↗

PubMedDate not supplied

Diagnosis and management of heterotopic pancreas.

Fifteen patients with 16 histologically verified heterotopic pancreas lesions were encountered at our department during a period of 22 years. The incidence was 0.25% of the findings of all abdominal operations during the same period. Heterotopic pancreas caused symptoms in 5 patients. All the remaining 10 patients were asymptomatic, whose lesions were found coincidentally at the time of surgery for other abdominal diseases. Heterotopic pancreas developed most frequently in the jejunum (46.7%). Preoperatively, only 2 lesions of the stomach in 2 patients were suspected to be heterotopic pancreas. At the time of operation, 10 of 16 lesions were diagnosed correctly on the basis of the macroscopic features. Malignant degeneration was seen in the duodenal and jejunal heterotopic pancreas. The former lesion was successfully resected by pancreatoduodenectomy. There were no deaths related to heterotopic pancreas or to the operations performed. Resection of the tissue-bearing area is advisable when the condition is encountered coincidentally at operation, and surgical exploration should be done for all symptomatic patients, particularly in the absence of histological diagnosis.

Choristoma↗

PubMedDate not supplied

In vitro antitumor activity of 4'-O-tetrahydropyranyladriamycin on human gastric cancer cells.

The antitumor activity of 4'-O-tetrahydropyranyladriamycin (THP-ADM) was assessed in established gastric cancer cell lines, including MKN-28, moderately differentiated adenocarcinoma and KATO-III, signet ring cell carcinoma and freshly excised human gastric cancer cells, using the MTT assay. The inhibition rates of THP-ADM were identical to those of adriamycin (ADM) in established gastric cancer cell lines, and the chemosensitivity of MKN-28 was higher than KATO-III. In fresh human gastric cancer cells obtained from 27 patients the inhibition rates of THP-ADM were identical to those of ADM, and there was a significant correlation of inhibition rates ADM and THP-ADM. These results indicate that THP-ADM should be a potent candidate to replace ADM in cancer chemotherapy.

Adenocarcinoma↗

PubMedDate not supplied

Etoposide enhances the antitumor effects of cisplatin in gastric cancer cells.

We studied the combination effect of cisplatin(CDDP) plus etoposide(VP-16) in an established gastric cancer cell line, KATO-III, and also highly purified fresh human tumor cells obtained from 55 gastric cancer patients, using MTT assay. The synergistic effects of CDDP plus VP-16 were shown by both the fractional product method and median effect plot analysis in KATO-III cells, and by fractional product method in fresh human gastric cancer cells. The combination with CDDP and VP-16 showed the synergistic antitumor effects in not only KATO-III cells, but also fresh human gastric cancer cells. The antitumor effects of CDDP were enhanced by early exposure of VP-16 in KATO-III cells. The combination effects of CDDP and VP-16 were more potent in poorly differentiated gastric cancer, compared with well-differentiated cell types. Thus, it is suggested that the combination of CDDP plus VP-16 is useful in the anticancer chemotherapy of gastric cancer patients.

Antineoplastic Combined Chemotherapy Protocols↗