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T Nakamoto

Publications and source records attributed to T Nakamoto.

244 records · Page 14Linked to original sources
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Protein-energy malnutrition alters theophylline effect on DNA synthesis in neonatal rat brain in vitro.

The rate of incorporation of [3H]-thymidine into DNA in whole brain in response to various concentrations of theophylline was studied in normal and malnourished neonatal rats in vitro. Malnutrition appeared to produce an increased sensitivity to theophylline. [3H]-Thymidine uptake was significantly increased in normally nourished animals at a concentration of 2 X 10(-4) mol/l (36 micrograms/ml), while malnourished animals showed a similar effect at 1 X 10(-4) mol/l (18 micrograms/ml). These data suggest that the nutritional status of a growing organ could be important determining the cellular effects of conventionally dosed theophylline under clinical conditions.

Animals↗
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Changes in sequestered leukocytes and platelets in the pulmonary microvasculature of rats with monocrotaline-induced pulmonary hypertension.

The role of leukocytes (WBCs) and platelets (PLTs) in the pulmonary circulation may be important in the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. We investigated the changes in WBCs and PLTs in the pulmonary microvasculature during the development of chronic pulmonary hypertension in MCT rats by real-time confocal scanning laser microscopy. The number of WBCs sequestered in the pulmonary microvasculature increased significantly from day 7 after MCT injection, but no further increase occurred from days 14-28. The number of PLTs sequestered in the pulmonary microvasculature increased significantly from day 7 after MCT injection, and reached a peak on day 14. However, the number of PLTs sequestered on days 21 and 28 after MCT injection was significantly lower than on day 14. These findings suggest that PLTs mainly contribute to the initial and middle stages of the development of MCT-induced pulmonary hypertension in rats, while WBCs mainly contribute to the middle and late stages.

Animals↗
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Pharmacokinetics of isolated hepatic perfusion with high dose tumor necrosis factor in rat model.

BACKGROUND: Although the application of an isolation procedure with tumor necrosis factor (TNF) to the liver is quite attractive, an animal model is not yet available to evaluate antitumor effects by TNF in isolated hepatic perfusion (IHP). To establish the rat model in IHP, the pharmacokinetics of TNF, both in a perfusate and in a systemic circuit should be examined. METHODS: All rats underwent IHP with TNF. After a 10 min perfusion, a washout procedure was performed for 5 min, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the systemic blood and concentrations of TNF were assayed by L-929 cytotoxicity. RESULTS: After the administration of 240 micrograms of TNF in the circuit, TNF reached a plateau at about 12.7 micrograms/ml of perfusion fluid, lasting until the end of IHP. As a result of the washout procedure, regional TNF concentrations declined from 12.7 micrograms/ml to 1.5 micrograms/ml. At the beginning of the IHP, all rats exhibited no detectable level of TNF activity in the systemic circulation (< 100 pg/ml). With time, TNF plasma levels quickly increased to reach a plateau of about 0.2 microgram/ml at 15 min. Systemic leakage of TNF is calculated as less than 2% of the total TNF in perfusate during perfusion. CONCLUSION: Rat IHP models with TNF showed that systemic leakage of TNF was higher than that of pig models, although a large enough amount of TNF in perfusate was achieved without death. Rat models might be feasible to evaluate antitumor effect of IHP against liver metastatic tumors.

Animals↗
PubMedDate not supplied

Reduction of hepatotoxicity of tumor necrosis factor in isolated hepatic perfusion by administration of glucocorticoid as well as lipopolysaccharide.

BACKGROUND: The application of an isolation procedure with tumor necrosis factor (TNF) to the liver is quit attractive, however, one of problems to overcome is reducing the toxicity to the liver caused by high doses of TNF. MATERIALS AND METHODS: Rats underwent isolated hepatic perfusion (IHP) with TNF and pre-treatment of subcutaneous administration of dexamethasone (4 mg/kg) and/or intradermal administration of LPS (50 micrograms/rat). After a 10 min perfusion, a washout procedure was performed for 5 min, after which isolation was terminated. RESULTS: SD or Wister rats and F344 rats tolerated up to 120 mg/rat or 4 micrograms/rat, respectively. Dexamethasone and/or LPS was tolerated at 40 micrograms/rat of TNF in F344 rat and showed a significant reduction of hepatotoxicity, and indicated histologically the suppression of ballooning and of necrosis during and after perfusion by TNF. CONCLUSION: We propose new a protocol for IHP as follows: 1. the intradermal administration of LPS for protection against toxicity of TNF, 2. IHP with TNF-SAM2, a mutain of TNF-alpha, having less toxicity than conventional TNF-alpha, and 3. simultaneous perfusion with chemotherapeutic agents such as 5-fluorouracil (5-FU).

Adult↗
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Relationship between microvessel quantification and inducibility of endogenous tumor necrosis factor in colorectal adenocarcinoma.

BACKGROUND: Although we have reported that the inducibility of endogenous tumor necrosis factor (en-TNF) by tumor cells is an independent prognostic factor in Dukes stage C colorectal cancer patients, the mechanism by which the patients having high inducibility of en-TNF show better prognosis is still unclear. We hypothesize that the inducibility of en-TNF by colorectal tumor cells affects the prognosis of patients through the modulation of angiogenesis. Thus, the aim of this study is to clarify the relationship between inducibility of en-TNF and tumor vascularity in colorectal cancer. PATIENTS AND METHODS: Histological sections from 62 Dukes stage C colorectal cancer patients who received curative operation were immunostained for CD34 antigen. Microvessels were counted in the photograph of x200 fields (0.298 mm2). The average count of five most vascular areas was determined as a microvessel density of each case. RESULTS: Two of 62 cases were excluded from the analysis, because of insufficient staining. A total of 60 patients were dichotomized by a median vessel count of 34 into two groups: 30 patients with lower microvessel density (Low MVD group) and 30 patients with higher microvessel density (High MVD group). There was no significance in the distribution of all clinicopathological factors among these two groups. Regarding en-TNF inducibility, no difference was shown between the two groups. The five year survival rate of Low MVD group and High MVD group were 58.7% and 68.0%, respectively. And, the 5 year relapse-free survival rate of Low MVD group and High MVD group were 59.7% and 52.2%, respectively. No significant difference was demonstrated between Low MVD group and High MVD group. CONCLUSION: Intratumoral microvessel density did not influence on the prognosis of colorectal cancer patients in Dukes stage C after curative operation. The inducibility of en-TNF showed no correlation with intratumoral microvessel density in Dukes stage C patients after curative operation.

Adenocarcinoma↗
PubMedDate not supplied

A new method of antitumor therapy with a high dose of TNF perfusion for unresectable liver tumors.

There are primary and secondary malignant liver tumors for which principal treatment is surgical resection. There is no established treatment for unresectable malignant liver tumors, however, and the prognosis for these is quite poor. An effective treatment for malignant liver tumors is thus urgently needed. Recent advances in molecular biology have uncovered the structures and/or functions of many cytokines thought to have a strong relation with the mechanisms of the antitumor effect of biological therapies. Availability of those cytokines in large amounts and homogeneously owing to advances in recombinant technology makes it possible to use them clinically. Among cytokines demonstrating antitumor activities, tumor necrosis factor-alpha (TNF-alpha) is one of the strongest. However, severe toxicity such as hypotension, abnormalities in liver function, leukopenia, chill and thrombus formation makes TNF-alpha difficult to use systemically as an antitumor drug. To enhance cytotoxicity while decreasing the side effects, especially hypotension, we developed a mutein called TNF-SAM2 by protein-engineering. The biological activity of TNF-SAM2 was more beneficial than TNF-alpha for antitumor therapy, since its side effects were milder. In contrast, using the isolated limb perfusion (ILP) method against malignant melanoma and soft tissue sarcoma of the extremities in combination with TNF-alpha and melphalan, a high response rate of 70-100% was observed. These observations led to the re-evaluation of TNF as an antitumor drug. A preliminary clinical trial was done using TNF-alpha combined with the formation of a closed circuit (isolated hepatic perfusion method) targeting the liver and a response rate of over 75% was achieved against malignant liver tumors. To isolate the liver from the systemic circulation, however, required a laparotomy, so that patients were subjected to excessive surgical stress. Isolated hypoxic hepatic perfusion (IHHP) using balloon catheters is a treatment developed to overcome such stress and we are planning to do clinical trials of IHHP with TNF-SAM2 in combination with a chemotherapeutic agent against malignant liver tumor patients. IHHP combined with TNF-SAM2 and a chemotherapeutic agent might be more beneficial in antitumor effects as well as in maintaining good quality of life (QOL) for the patient.

Animals↗
PubMedDate not supplied

Mechanisms by which chemotherapeutic agents augment the antitumor effects of tumor necrosis factor: involvement of the pattern shift of cytokines from Th2 to Th1 in tumor lesions.

BACKGROUND: The antitumor effect exerted by tumor necrosis factor (TNF) is characteristic in that it causes central necrosis of the tumor mass. Viable tumor cells surrounding the tumor mass remain, however, even after most of the mass is necrotized, and these cells gradually regrow and form tumors. To overcome this, we analyzed the combined effects of chemotherapeutic agents used with TNF. Alkylating agents such as cyclophosphamide altered the antitumor effect qualitatively, leading to complete regression which TNF alone could not achieve. The mechanism, behind the enhancement of endogenous TNF production and expression of mRNA of various cytokines by the combination of chemotherapeutic agents with TNF inducer was investigated in Meth A fibrosarcoma. METHODS: Seven days after the inoculation of Meth A fibrosarcoma into BALB/c mice, cyclophosphamide (CY, 100-150 mg/kg) was injected intraperitoneally, and 7 days later endogenous TNF was induced by the intradermal administration of lipopolysaccharide (LPS, 400 micrograms/kg) or intravenous injection of ONO-4007, a synthetic lipid A derivative (30 mg/kg). RESULTS: A combination therapy of LPS or ONO-4007 with CY showed the effect of complete regression in 50-100% of tested mice, while CY, LPSp or ONO-4007 alone did not cause complete regression. The amount of endogenous TNF induced by LPSp or ONO-4007 around a tumor lesion with CY was 4-5 fold higher than that without CY. The expression of mRNA of transforming growth factor-beta was suppressed by CY seven days after the injection, and expressions of mRNA of IL-1 beta and TNF-alpha were augmented by the administration of CY 1 to 3 hours after the administration of ONO-4007. CONCLUSION: Some chemotherapeutic agents thus appear to augment the antitumor effect of TNF around tumor lesions, leading to tumor regression through a mechanism in which the agent changes the host's immune status, especially around a tumor lesion and pattern shift of cytokines from Th2 to Th1.

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