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2.
J Exp Clin Cancer Res ; 25(1): 79-82, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16761622

ABSTRACT

5-fluorouracil (5-FU) is mostly metabolized after administration, and the metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD), seems to be the rate-limiting factor. However, there are few reports on the final metabolite, fluoro-beta-alanine (FBAL). We report here the results of determination of the FBAL level in 5-FU treated patients and the correlation between the FBAL level and the DPD activity in peripheral blood mononuclear cells (PBMCs). Blood samples were collected from 20 patients, who had received continuous intravenous infusion (CIV) of 5-FU (320 mg/m2/24 hr) after resection of colorectal cancer, and the FBAL level was determined by high performance liquid chromatography (HPLC), after derivatizing into o-phthalaldehyde (OPA) and detecting fluorescence. DPD activity was measured in cytosol prepared from PBMCs using HPLC radioassay. The average FBAL plasma level during CIV of 5-FU was 911.0 ng/ml (521.0 to approximately 1834.6 ng/ml) and that of DPD activity in PBMCs was 282.6 pmol/min/mg-protein (145.0 to approximately 568.0 pmol/min/mg-protein). There was a significant correlation between the FBAL level and the DPD activity (r=0.805, p<0.0001). FBAL level in plasma may be useful in predicting the DPD activity in PBMCs, however, further studies are required considering the small number of cases in this study.


Subject(s)
Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Fluorouracil/blood , Fluorouracil/therapeutic use , Leukocytes, Mononuclear/cytology , Aged , Alanine/analogs & derivatives , Alanine/chemistry , Chromatography, High Pressure Liquid , Combined Modality Therapy , Dihydrouracil Dehydrogenase (NADP)/metabolism , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , o-Phthalaldehyde/pharmacology
3.
J Exp Clin Cancer Res ; 24(3): 439-46, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16270531

ABSTRACT

In the present study, we investigated the effect of the RANTES-mediated interaction between gastric carcinoma cell lines and peripheral blood mononuclear cells (PBMCs) in tumor progression. RANTES production in PBMCs stimulated by highly metastatic cancer cell line-conditioned supernatants was higher than in those stimulated by a less metastatic gastric cancer cell line-conditioned supernatant. RANTES receptors were expressed in PBMCs, but not in those cancer cell lines; therefore it was suggested that RANTES might affect PBMCs but not cancer cells. Matrix metalloproteinase (MMP)-9 expression in PBMCs was examined. Similar to RANTES production, MMP-9 expression in PBMCs stimulated by highly metastatic cell line-conditioned supernatants was higher than in that stimulated by a less metastatic cell line-conditioned supernatant. Invasion assays of gastric cancer cell lines were performed. Cancer cells cultured with PBMCs invaded into Matrigel more frequently than those without PBMCs. This invasive activity was highly inhibited by an anti-RANTES antibody. These results suggest that tumor cells can acquire the potential for invasion by cooperating with PBMCs and RANTES plays an important role in the interplay between tumor cells and PBMCs. It is thus thought that RANTES might be a candidate molecular target in the therapeutic strategy for gastric cancers.


Subject(s)
Chemokine CCL5/physiology , Monocytes/physiology , Stomach Neoplasms/pathology , Base Sequence , Cell Line, Tumor , Coculture Techniques , Culture Media, Conditioned , DNA Primers , Disease Progression , Humans , Matrix Metalloproteinase 9/genetics , Neoplasm Invasiveness , RNA, Messenger/genetics , Receptors, CCR5 , Receptors, Chemokine/physiology , Stomach Neoplasms/enzymology , Stomach Neoplasms/physiopathology
4.
Transplant Proc ; 37(1): 417-21, 2005.
Article in English | MEDLINE | ID: mdl-15808663

ABSTRACT

BACKGROUND: Ischemia-reperfusion (I/R) injury occurs in various situations, including transplantation, trauma, and shock. We previously reported that the synthetic beta-SQDG (18:0), which was derived from sulfoquinovosyl diacylglycerol of the sea urchin, possessed immunosuppressive effects, such as inhibition of T-cell responses in human allogenic human mixed lymphocyte reactions (MLR) and skin allograft survival in rats. beta-SQAG9 was synthesized from beta-SQDG (18:0) to improve structural stability in aqueous solution with the same biological activities to bind to CD62L (L-selectin) and CD62P (P-selectin) in vitro. We hypothesized that beta-SQAG9 might attenuate leukocyte rolling on the endothelium and neutrophil infiltration in which L-selectin and P-selectin are key molecules. We investigated the protective effect of beta-SQAG9 against hepatic I/R injury. METHODS: Male Lewis rats were divided into 6 groups: sham, control, and treatment. Rats in the control, and the treatment groups were subjected to hepatic ischemia for 30 minutes. They were injected with PBS or beta-SQAG9 at doses of 5, 10, 25, and 50 mg/kg into the penile vein immediately before reperfusion. To assess the damage to the hepatic parenchyma, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were measured and histological evaluation was performed at 6 hours after reperfusion. RESULTS: In the group treated with beta-SQAG9 at a dose of 10 mg/kg, AST, ALT, and LDH were significantly reduced, and the amount of neutrophil infiltration also was significantly reduced. CONCLUSIONS: Our data suggest that SQAG-9 (10 mg/kg) reduces the warm hepatic I/R injury.


Subject(s)
Glycolipids/therapeutic use , Liver Circulation , Reperfusion Injury/prevention & control , Animals , Glycolipids/isolation & purification , Immunosuppressive Agents/isolation & purification , Immunosuppressive Agents/therapeutic use , Liposomes , Liver/drug effects , Liver/pathology , Male , Necrosis , Neutrophils/pathology , Rats , Rats, Inbred Lew , Sea Urchins
5.
Transplant Proc ; 36(7): 1965-9, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15518713

ABSTRACT

BACKGROUND: In hepatic surgery and liver transplantation, ischemia-reperfusion (I/R) is an unavoidable process, and protection against hepatic I/R injury is a major unresolved problem. In this study, we investigated whether 3-O-(6-deoxy-6-sulfono-beta-D-glucopyranosyl)-1,2-di-O-acylglycerol bound to saturated C18 fatty acids (beta-SQAG9), which was derived from sea urchin intestines, could reduce this injury. This agent was recently reported to have immunosuppressive effects in allogeneic rat skin grafts. MATERIALS & METHODS: Male Lewis rats were divided into two experimental groups. Group 1 rats were injected with SQAG9 (50 mg/kg) into the penile vein 15 minutes before the induction of ischemia and into the portal vein just reperfusion. The same amounts of normal saline were injected into rats in the control group (group 2). Each experimental groups included six rats. Seventy percent hepatic ischemia (20 minutes) was induced by occluding the blood vessels and bile duct with a vascular clamp. For examination of hepatic function, serum levels of aspartate aminotransferase, (AST) alanine transaminase (ALT), and lactic dehydrogenase (LDH) were measured. In addition, histological examination was also assessed. RESULTS: Three hours after reperfusion, the mean plasma concentration of AST, ALT, LDH in group 1 was suppressed compared with group 2. Six hours after reperfusion, the hepatic damage in group 1 was mild in comparison with that in group 2. CONCLUSIONS: Our data demonstrated that SQAG-9 reduced the warm hepatic I/R injury.


Subject(s)
Diglycerides/pharmacology , Glycolipids/pharmacology , Liver Circulation/drug effects , Liver , Reperfusion Injury/prevention & control , Animals , Liver/blood supply , Liver/drug effects , Liver/pathology , Liver Function Tests , Male , Rats , Rats, Inbred Lew , Sea Urchins/metabolism
11.
Surgery ; 125(4): 385-95, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10216529

ABSTRACT

BACKGROUND: The protective effects of heat-shock protein (hsp) in rat small intestinal warm ischemia-reperfusion (I/R) injury are poorly understood. METHODS: Hsp-73 expression was induced in rat small intestine with use of sodium arsenite injected (6 mg/kg) through a catheter cannulated into the left common carotid artery 24 hours before ischemia (group 1). In the control group an equal volume of phosphate-buffered saline solution was injected (group 2). To block the induction of hsp-73 expression, sodium arsenate and quercetin (5 mg/kg) were injected (group 3). RESULTS: The mean peak plasma levels of tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant after reperfusion were lower in group 1 than in group 2. The tissue myeloperoxidase activity after reperfusion was lower in group 1 than in group 2. The mean peak plasma level of interleukin-10 after reperfusion was higher in group 1 than in group 2. The induction of hsp-73 expression reduced the synthesis of nitric oxide and the magnitude of the small intestinal warm I/R injury. The results in group 3 were similar to those in group 2. CONCLUSION: Hsp-73 protects against small intestinal warm I/R injury by inhibiting the synthesis of inflammatory cytokines and the activation of neutrophils and by accelerating the synthesis of anti-inflammatory cytokines.


Subject(s)
Chemokines, CXC , Heat-Shock Proteins/physiology , Intercellular Signaling Peptides and Proteins , Intestine, Small/blood supply , Intestine, Small/surgery , Reperfusion Injury/prevention & control , Animals , Arsenites/pharmacology , Blotting, Western , Chemotactic Factors/biosynthesis , Chemotactic Factors/blood , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Growth Inhibitors/biosynthesis , Growth Inhibitors/blood , Growth Substances/biosynthesis , Growth Substances/blood , Heat-Shock Proteins/analysis , Hot Temperature , Interleukin-10/biosynthesis , Interleukin-10/blood , Intestinal Mucosa/blood supply , Intestinal Mucosa/enzymology , Intestinal Mucosa/surgery , Intestine, Small/enzymology , Male , Nitric Oxide/biosynthesis , Nitric Oxide/blood , Peroxidase/metabolism , Quercetin/pharmacology , Rats , Rats, Inbred Lew , Reperfusion Injury/chemically induced , Sodium Compounds/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/metabolism
14.
Gan To Kagaku Ryoho ; 26 Suppl 2: 333-7, 1999 Dec.
Article in Japanese | MEDLINE | ID: mdl-10630243

ABSTRACT

It is widely accepted that home chemotherapy improves the quality of life (QOL) of patients. Its purpose is to prevent the growth of the tumor rather than to reduce it is size, that is long NC, and to lessen the symptoms. The most important thing is side-effect-free treatment, because the patient is usually in the home. For this reason, the patient him/herself must be familiar with the side effects and emergency situations. Evaluation of home chemotherapy is very difficult, because the amount of anticancer drug is reduced or optimized for the individual patient. Thus, evaluation depends not only on tumor size, but also on QOL, lessening of symptoms, satisfaction or dissatisfaction with the treatment, and the philosophy of life of patients. This approach is being put to greater and greater use to maintain the QOL of patients, and to reduce the hospital costs. In the future, new anticancer drugs that have fewer side effects and stronger anticancer action are desirable.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Colonic Neoplasms/drug therapy , Home Infusion Therapy/standards , Liver Neoplasms/drug therapy , Adult , Female , Humans , Informed Consent , Infusions, Intra-Arterial , Male , Middle Aged , Quality of Life
15.
Cell Immunol ; 198(2): 103-10, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10648124

ABSTRACT

We examined the effect of exogenous IL-10 on the sensitivity of rat W14 and W31 tumor cells to natural killer (NK) cell-mediated cytotoxicity in relation to previously identified NK target structure (NKTS) expressed on these cells. We also examined the effect of endogenous interleukin-10 (IL-10) on rat IL-10 cDNA-introduced W31 cells (W31T-H, a high-IL-10-producer clone; W31T-L, a low-IL-10-producer clone). Both exogenous and endogenous IL-10 had no effect on the proliferative activity of these cells, but incubation of cells with recombinant human (rh) IL-10 resulted in a dose-dependent decrease in the expression of NKTS recognized by mAb 109. The expression level of NKTS on W31T-H cells was dramatically decreased compared with that on W31T-L cells and parental W31 cells. In addition, treatment of W31 cells with the culture supernatants of W31T-H cells could downregulate the expression of the NKTS. Moreover, NK sensitivity of W31T-H was suppressed down to a level equivalent to that of W31 cells pretreated with exogenous rhIL-10, and cytolysis could no longer be inhibited by mAb 109. We previously demonstrated that IL-10 downregulated MHC class I expression in this model. Nevertheless, NK susceptibility was also decreased. Taken together, these results suggest that the IL-10-mediated decrease in NKTS expression has a larger effect than decreased MHC class I expression on NK sensitivity. Thus, our data reveal a novel mechanism for an IL-10-mediated escape of tumor cells from host immune surveillance by downregulation of NKTS expression.


Subject(s)
Cytotoxicity, Immunologic/drug effects , Interleukin-10/pharmacology , Killer Cells, Natural/drug effects , Neoplasms, Experimental/immunology , Animals , Antibodies, Monoclonal/immunology , Down-Regulation , Histocompatibility Antigens Class I/physiology , Immunohistochemistry , Killer Cells, Natural/immunology , Male , Mice , Mice, Inbred BALB C , Rats , Rats, Inbred Strains , Recombinant Proteins/pharmacology
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