5-Ethyl-2′-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil

The aim of the present studies was to elucidate the effects and optimal modulatory conditions of 5-ethyl-2′-deoxyuridine (EtdUrd) on the antitumour efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine in the plasma and that of 5-FU and 5-fluoro-2′-deoxyuridine monophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively enhanced the antitumour action of 5-FU, without significantly increasing its toxic side-effects, thus resulting in an approximately three times higher therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg EtdUrd administration – i.e. at the time of 5-FU treatment – the plasma concentration of EtdUrd was 269 μM, and that of 5-ethyluracil, as the major metabolite of EtdUrd, was 421 μM. It is of interest that EtdUrd pretreatment did not change the maximal plasma concentration of 5-FU; however, the half-life of the terminal elimination increased from 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose significantly (P < 0.05). After the combined treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma decreased from 61.06 μM to 29.70 μM (P < 0.01). The intratumoral concentrations of 5-FU were 34%–158% higher 6–96 h after the combined treatment than after the single 5-FU treatment. EtdUrd also caused a moderate increase in the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concentration in the plasma from 18 μM to a maximum of 249 μM, and the level remained high for longer than 6 h. The present studies indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at the same time, offering protection to normal organs by increasing the endogenous uridine level. Received: 24 March 1999 / Accepted: 21 June 1999     

Primary gastric tuberculosis – report of 5 cases

Background  

Gastric tuberculosis is rare, and usually associated with pulmonary tuberculosis or an immunodeficient state. Here, we report five cases of gastric tuberculosis in immunocompetent patients without evidence of pulmonary involvement.     

Summary of the 5th Annual Scientific Session of Cardiology in South China

The 5th Annual Scientific Session of Cardiology inSouth China was held from April 3—7.2003 inGuangzhou.A seminar——“The Frontline Problemsand New Viewpoints in Cardiology in Recent Times”was held at the same time.More than one thousandcardiology specialists came from south and middleChina to participate in the meeting and 135 papers were     

Retrospective analysis of 186 cases of upper gastrointestinal bleeding in recent 5 years

Ｒｅｔｒｏｓｐｅｃｔｉｖｅａｎａｌｙｓｉｓｏｆ１８６ｃａｓｅｓｏｆｕｐｐｅｒｇａｓｔｒｏｉｎｔｅｓｔｉｎａｌｂｌｅｅｄｉｎｇｉｎｒｅｃｅｎｔ５ｙｅａｒｓＬＩＡＯＣｈａｎｇＫｕｉ，ＸＩＥＹｏｕＲｏｎｇａｎｄＬＵＱｉａｏＬｉａｎＳｕｂｊｅｃｔｈｅａ...     

Arterial chemotherapy of 5—fluorouracil and mitomycin Cin the treatment of liver metastases of colorectal cancer

AIM：Regional chemotherapy using hepatic artery catheters is a good method of treating patients with colorectal cancer liver metastases.We investigated the survival of patients with liver metastases from colorectal cancer using 5-fluorouracil(5-FU)and mitomycin C Cthrough implantable hepatic arterial infusion port.METHODS:Seventy-five patents with inoperable liver metastases forom colorectal cancer were included between March,1992 and November,2001,We placed implantable hepatic arterial cathter(HAC)port by laparotomy,5-FU,1000mg/m^2/d continuors infusion for five days every four weeks,was delivered in the hepatic arterial catheter through the port.Mitomycin C,30mg/m^2/d infusion in the first day every cycel through the port.Response to the treatment was evaluated by serial determinations of plasma CEAand imaping techniques consisting of computerized tomography and sonography of liver.RESULTS:Sixty-eight were performed hepatic artery chemotherapy and fifty-six were followed up among seventy-five HAC patients.Twenty-six patients(46.4%)have responded and4complete remission were achieved.Eight patients(14.3%)had stable liver metastases.Twenty-two patients(39.3%)were progressed with increased tumor size and number.Twenty-nine patients(51.8%)had a decreased serum CEAlevel.while10patients(17.9%) were stable and 17patients(30.4%)had an increased serum CEAlevel.There were no operative death in this serise.Complications,which occurred in 18patients(32.1%),were as followed:hepatic artery thrombosis in11,Upper gastric and intestinal bleeding in3,liver abscess in1,pocket infection in1,cholangitis in1,and hepatic artery pseudo-aneurysm in one patient.CONCLUSION:Combined infusion of 5-FU and mitomycin C by hepatic artery catheter port is an effective treatment for liver metastases from colorectal cancer.The high response and lower complication rater prove the adjuvant treatment of colorectal cancer with this treatment.     

Involvement of α5 integrin in survivin-mediated osteosarcoma metastasis

Objective: To investigate the role of survivin in osteosarcoma metastasis. Methods: Small interfering RNA(si RNA) was used to knockdown the expression of survivin and α5 integrin in the human osteosarcoma cell line MG63. Western blotting and immunostaining methods was used to assessed the effect of survivin knockdown on the expression of α5 integrin through flow cytometry and fluorescence microscopy detection. Meanwhile, the invasion and migration of transfected cells in Transwell and wound healing assays were probed, and the growth situation of these cells transplanted into nude mice was monitored. Results: Knockdown of survivin expression could inhibit the invasion and migration of osteosarcoma MG64 cells in vitro and the expression of α5 integrin on osteosarcoma MG64 cell surface, suggesting that survivin can inhibit the invasion and migration of osteosarcoma cells through downregulation of α5 integrin. Anti-α5 integrin antibody could also markedly decrease the capability of invasion and migration of osteosarcoma MG64 cells. Additionally, knockdown of survivin expression could slow the growth of osteosarcoma MG63 cells transplanted into nude mice. Conclusions: Survivin-directed anti-tumor strategies might be an effective method in the treatment of osteosarcoma.     

Deficiency of pyrimidine 5′-nucleotidase in human leukocytes

Summary Both erythrocytes and leukocytes from a patient with erythrocyte pyrimidine 5-nucleotidase (P5N) deficiency were shown to contain increased amounts of pyrimidine nucleotides. These findings suggested that the leukocytes were also deficient for P5N. Measurement of the P5N activity in lysates from lymphocytes or granulocytes, in the presence of inhibitors for non-specific 5-nucleotidase or alkaline phosphatase, indeed showed a deficiency for P5N in lymphocytes and granulocytes of the patient with erythrocyte P5N deficiency. However, the P5N deficiency in the leukocytes did not cause clinical disturbances in addition to the weak haemolytic anaemia.     

Gradual upregulation of OCI-5 expression during occurrence and progression of rat hepatocellular carcinoma

BACKGROUND: OCI-5, the rat homologene of human glypican 3 ( GPC3), is confirmed upregulated in hepatocellular carcinoma (HCC). The present study was undertaken to detect gene expression change of OCI-5 during occurrence and progression of rat HCC. METHODS: Male Sprague-Dawley rats were given diethyl-nitrosamine ( DENA) to induce HCC. Three DENA-induced rats and one control rat were sacrificed every week for 18 weeks during the development of HCC. Tissues specimens were snap-frozen in liquid nitrogen and total RNA was isolated. Sk-Hepl cells were treated with DENA at different concentrations. The gene expression levels of OCI-5 and GPC3 were detected with the RT-PCR method. RESULTS: OCI-5 was not expressed in normal rat liver tissues. When HCC occurred and aggravated, OCI-5 expression was gradually elevated to a very high level. GPC3 was not expressed in the DENA-treated Sk-Hepl cells. CONCLUSIONS: OCI-5 was not expressed in normal rat liver tissues but in rat HCC tissues. High-expression of OCI-5 in DENA-induced rat HCC model was the gene expression change of HCC not the DENA-induced gene expression. The expression level of OCI-5 was not only elevated in rat HCC but also gradually along the occurrence and progression of HCC, indicating that GPC3 might serve as a sensitive marker of early stage HCC.     

Effect of pentagastrin on IL-11β5 induced inhibition of insulin secretion inneonatal rat islets of Langerhans

AIM To obserwe tb e effect of pentagastrin (G-5) on IL-1β induced inhibition of insulin secretion in newbornrat islet of Langerhans.METHODS Islets of Langerhans of 3- to 5-day-old rats were isolated by collagenase digestion. The isletswere maintained free-floating in culture medium RPMI-1640, containing 10% (V/V) calf serum, anddistributed randomly in 96-well plastic plates (6 wells in each group). There are 15 islets per well in 0.2 mLculture medium. The islets were kept at 37℃ in mixed gases of 5% CO2 and 95% humidified air for the timerequired by the experimental design. Three experiments were performed in this study. (①) IL-13 inducedinhibition of insulin secretion in isolated islets of Langerhans. (②) Effect of G-5 on IL-lβ induced inhibition ofinsulin secretion. ③ Effect of G-5 on the functional repair of islet B-cells inhibited by IL-1β. Accumulatedand glucose stimulated insulin secretion was measured by radioimmunoassay in all studies. Data are presentedas ~ ± s. Differences between groups were analyzed using the Student's t test. P <0.05 was consideredsignificant.RESULTS The function of islet B-cells, which has been received 1L-1β treated for 24 hours, was dose-dependently inhibited. The accumulated and glucose stimulated insulin secretion was significantly lower thanthat of the control group (P<0. 05). The inhibitory effect of IL-1β on islet B-cells can be partially reversedby G-5. Accumulated and stimulated insulin secretion of G-5 0.6 ng/mL and 0.8 ng/mL groups wassignificantly higher than that of IL-1β treated alone group (P<0.05). The function of islet B-cells, whichreceived IL-iβ treatment for 24 hours, could partially recover after G-5 treatment for another 24 hours. Butaccumulated and glucose-stimulated insulin secretion in groups with G-5 treatment for 10 hours groups had nosignificant difference as compared with IL-1β treated alone group (P>0.05).CONCLUSION The present results indicate that G-5 may have a protective effect against the toxicity of IL-1β on islet B-cells.     

Characterization of three new deletions at the 5′ end of the HPRT structural gene

Summary In a panel of seven unrelated HPRT-deficient patients three partial deletions of the 5 end of the HPRT structural gene were identified by Southern blot analysis. The deletions could be defined as the loss of exons 1–3, exons 2–3 and exon 3 respectively. In two of the deletion mutations aberrant restriction fragments occurred.Presented at a symposium on inherited metabolic diseases at Brno in 1989.     

2022年Journal of Diabetes第5期中文导读

综述/Review Article     

Elevated Oxidative Stress in the Brain of Senescence-accelerated Mice at 5 Months of Age

The senescence-accelerated mouse (SAM) is a useful animal model to study aging or age-associated disorder. In the present study, we have used a multidisciplinary approach to the characterization of changes that occur in aging and in the modelling of brain aging. The SAMP8 mouse at 5 months of age exhibited an increase in gliosis and molecular oxidative damage. Likewise, we found that superoxide dismutase activity decreased compared with age-matched SAMR1 while there were no differences in activity of catalase and glutathione reductase. These results indicate that the decrease of superoxide dismutase may be involved in the increase of oxidative stress in brain of SAMP8 at younger stages. This suggestion is supported by an increase in the expression of alpha-synuclein together with phosphorylated tau protein, which is concurrent with the decline of that antioxidant enzyme. Alpha-synuclein aggregates are invariably associated with tau pathologies and our results demonstrate that alpha-synuclein accumulation is a potent inducer of tau pathologies not only in neurodegenerative diseases but also in normal aging. These results also imply that SAMP8 are exposed to elevated levels of oxidative stress from an early age, and that could be a very important cause of the senescence-related impairments and degeneration in the brain seen in this strain. Mercè Pallàs, Ana Coto-Montes: Joint senior authorship.     

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-a

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-α (PEG-IFN-α). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-α was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-a and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-α with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.     

Point mutation of 5＇ noncoding region of BCL-6 gene in primary gastric lymphomas

AIM: To investigate the mutations of the 5' noncoding region of BCL-6 gene in Chinese patients with primary gastric lymphomas. METHODS: PCR and direct DNA sequencing were used to identify BCL-6 gene mutations in the 5' noncoding region in 29 cases of gastric diffuse large B-cell lymphoma (DLBCL) and 18 cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma as well as 10 cases of reactive hyperplasia of lymph node (LRH). RESULTS: Six of 29 gastric DLBCLs (20.7%), 4 of 18 gastric MALT lymphomas (22.2%) and 1 of 10 LRHs(10%) were found to have mutations. All mutations were single-base substitutions and the frequency of single-base changes was 0.20×1O~(-2)-1.02×1O~(-2)per bp. CONCLUSION: Point mutations in the 5' noncoding region of BCL-6 gene are found in Chinese patients with primary gastric DLBCLs and MALT lymphomas, suggesting that they may, in some extent, participate in the pathogenesis of primary gastric DLBCLs and MALT lymphomas.