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ABSTRACT: Type I interferons (IFNs) play a pivotal role not only in antiviral immunity but also in the surveillance of cancer development. In order to quantify the critical function of type I IFNs in the suppression of human cancer development, IFN-alpha production in response to Sendai virus stimulation has been compared between healthy control subjects and hepatitis C virus (HCV)-infected patients, the latter being an ideal population for longterm monitoring of cancer development. Data for IFN-alpha production were obtained retrospectively over a 17-year period by examining medical records in a study population of 2315 individuals, of which 112 healthy controls and 20 HCV-infected patients were selected. Sixty percent of the HCV-infected patients had impaired or declining IFN-alpha production, in comparison to 17% in the healthy control group. Mean IFN-alpha levels were lower in patients who developed hepatocellular carcinoma than in the HCV-infected patients who remained cancer free. Our findings suggest that impairment of IFN-alpha production may be linked to an increased cancer risk and that dysfunction of the IFN system is associated with some types of cancer. Therefore, periodic assessment and quantification of IFN-alpha production can be a potential test for the early detection of cancer in humans.
Journal of Interferon & Cytokine Research 01/2008; 27(12):1013-7. · 3.06 Impact Factor
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ABSTRACT: Research progress on the pleiotropic effects of interferons (IFN) has thus far required detecting responses by weak IFN signals. The activity of 2',5'-oligoadenylate synthetase (2-5OAS) is a valuable indicator in the prognosis and IFN treatment of patients with viral diseases such as hepatitis B and C. Although serum samples generally are used to measure enzyme activity, their values depend on the exact conditions under which blood is stored and the degree of haemolysis that occurs during blood drawing or serum separation. This study presents an improved method of evaluating 2-5OAS activity by using whole blood samples containing heparin, which are frozen and then thawed, instead of serum samples. This method is more reliable, convenient, and 50-100 times more sensitive than the conventional methods of measuring serum 2-5OAS activity. The reliability and sensitivity of this improved method enables detection of the effects of low doses of oral IFN administration or changes in the IFN and cytokine system by infection or autoimmune diseases.
Journal of Virological Methods 10/2006; 136(1-2):185-92. · 2.01 Impact Factor
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ABSTRACT: To determine the utility of interferon (IFN)-alpha production capacity in patients with hepatitis C virus (HCV) infection for the measurement of immuno-surveillance potential and for the early detection of hepatocellular carcinoma (HCC) by investigating the Sendai virus (HVJ) stimulated IFN-alpha production capacity of patients with HCV infection.
HVJ stimulated IFN-alpha production was determined in a large number of patients with HCV infection and the development of HCC was monitored for 3 years in patients with liver cirrhosis (LC).
IFN-alpha production capacity decreases gradually with the progression of liver disease from chronic hepatitis (CH) to HCC. A significant correlation between the duration of HCV infection and impaired IFN-alpha production capacity was observed. IFN-alpha production in patients who developed HCC within 3 years was significantly lower than that of patients who remained in LC without developing HCC.
Measurement of IFN-alpha production in LC patients may be useful for the early detection of HCC.
World Journal of Gastroenterology 01/2006; 11(46):7330-4. · 2.47 Impact Factor
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ABSTRACT: Interferon alpha (IFN-alpha), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-alpha patch preparations. The intestinal absorption of IFN-alpha was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-alpha levels were measured by an ELISA method and both C(max) and AUC were determined as the index of absorption of IFN-alpha. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C(max), 7.66 +/- 0.82 IU/ml, and AUC, 12.85 +/- 1.49 IU h/ml, than Labrasol (6.51 +/- 0.89 and 8.30 +/- 1.34 IU h/ml) and HCO-60 (6.02 +/- 1.14, 7.53 +/- 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-alpha to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-alpha is released from the patches, were 3.4 +/- 0.1 min for HCO-60, 7.8 +/- 0.1 min for Gelucire44/14 and 11.4 +/- 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-alpha dose from 50,000 to 25,000 IU/kg, the serum IFN-alpha levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-alpha has been proved in rats.
Journal of Drug Targeting 08/2005; 13(6):383-90. · 2.70 Impact Factor
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Yoshitaka Nakamura,
Hitoshi Fujiwara,
Teruhisa Sonoyama,
Toshiya Ochiai,
Takeshi Shimizu,
Daisuke Ichikawa,
Kazuma Okamoto,
Chouhei Sakakura,
Yuji Ueda,
Hirosumi Itoi,
Eigo Otsuji,
Akeo Hagiwara,
Hisakazu Yamagishi,
Yoko Mitsuishi, Tsunataro Kishida
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ABSTRACT: The patient was a 76-year-old man, diagnosed with sigmoid colon cancer with unresectable multible liver metastases. After sigmoidectomy with D2 regional lymphnode dissection on June 21, 2002 (moderately differentiated adenocarcinoma, ss, n(-), H3, P0, M(-), Stage IV), intermittent hepatic arterial infusion chemotherapy using 5-FU (1,250 mg/body/3 hr) and CDDP (10 mg/body/30 min) was performed weekly for 23 times, and then biweekly for 15 times. The total dosages of 5-FU were 47.5 g. During the regional chemotherapy, IFNANK therapy was performed biweekly as systemic immunotherapy. As a result, serum levels of tumor markers were remarkably decreased, and the metastatic liver tumors had disappeared in the CT finding in July 2003. Thereafter, IFNANK therapy was continued without the chemotherapy. However, CT and PET detected the recurrent liver tumors in December 2003, and the tumors were curatively resected on January 28, 2004.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2004; 31(11):1812-4.
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ABSTRACT: The induction of interleukin-12 (IL-12) responsiveness in T cells depends on T cell receptor (TCR) triggering, and is regarded as a parameter of recently TCR-sensitized T cells. Here, we investigated whether IL-12 responsiveness could be detected in freshly prepared T cells from tumor-bearing patients, and if so whether such patients exhibited additional immunological parameters related to IL-12 responsiveness. CD4(+) and CD8(+) T cell populations from an appreciable proportion of tumor-bearing patients exhibited high levels of IL-12 responsiveness as evaluated by IL-12-stimulated interferon-gamma (IFN-gamma) production. T cell populations with high IL-12 responsiveness were observed in the group of patients with moderate to large tumor mass or tumor metastases rather than in patients with small tumors. The frequency of such a T cell population was also lower in post-surgery tumor-free patients, showing the correlation between IL-12 responsiveness and the presence of a certain extent of tumor burden. More importantly, a higher incidence of IL-12 responsiveness was observed in tumor-bearing patients exhibiting detectable plasma IL-12 levels, and correlated with IL-18 responsiveness. T cell IL-12 and IL-18 responsiveness is induced by TCR triggering and subsequent IL-12 stimulation respectively. Furthermore, TCR-triggered T cells stimulate antigen-presenting cells (APC) to produce IL-12. Therefore, the present observations suggest that an immune response loop from TCR sensitization to the induction of IL-12/IL-18 responsiveness via IL-12 production operates in tumor-bearing patients, particularly in those with relatively large tumor burdens.
Cancer Immunology and Immunotherapy 02/2003; 52(1):33-40. · 3.70 Impact Factor
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ABSTRACT: Granulysin has been identified as an effector molecule co-localized with perforin in the cytotoxic granules of cytotoxic T lymphocytes and natural killer (NK) cells, and has been reported to kill intracellular pathogens in infected cells in the presence of perforin and to induce a cytotoxic effect against tumor cells. The aim of the present study was to elucidate whether intracellular expression of granulysin and perforin by NK cells might be associated with progression of cancer. Flow cytometric analysis demonstrated high levels of perforin and granulysin expression by CD3(-) CD16(+) cells in healthy controls. In contrast, cancer patients exhibited significantly decreased levels of granulysin expression ( P<0.005), despite having equally high levels of perforin expression in comparison with healthy controls. The tumor-free patients expressed granulysin at levels similar to healthy controls, while the progressive tumor-bearing patients expressed remarkably lower levels of granulysin compared to healthy controls ( P<0.0001). Similarly, patients with an advanced performance status had significantly fewer granulysin-positive NK cells than healthy controls. Meanwhile, a considerable number of the tumor-bearing patients showed a decrease in the number of circulating NK cells, and a correlation between impaired granulysin expression and reduced circulating NK cells was observed. These findings suggest that the tumor-bearing patients with impaired granulysin expression were in an immunosuppressive state. In conclusion, impaired expression of granulysin by NK cells correlates with progression of cancer, and determination of granulysin expression might prove informative for assessing the immunological condition of cancer patients.
Cancer Immunology and Immunotherapy 02/2002; 50(11):604-14. · 3.70 Impact Factor
