Studies on constituents of Korean basidiomycetes (L)

To find antitumor metabolites in Korean basidiomycetes, the shake-cultured mycelia of eight of the higher fungi were extracted with hot water and the extracts, after being partially purified, were subjected toin vivo antitumor test. When administeredi.p. at the dose of 30mg/kg/day for ten consecutive days into the female ICR mice, which had been implanted with 1×10⁵ cells of sarcoma 180 twenty-four hours before the first injection, the extracts ofAgaricus campestris, Lyophyllum decastes, Lyophyllum ulmarium, Armillaria tabescence andCalvatia exipulitormis respectively showed inhibition ratios of 64.1%, 65.4%, 60.0%, 53.0% and 49.3%. These five species were selected for further study, whereas the extracts ofPhallus impudicus, Coprinus comatus andPholiota squarrosa which showed the inhibition ratios of 31.2%, 33.5% and 19.0% were discontinued.     

Hybrid Pharmacokinetic Models to Describe Anti-HIV Nucleoside Brain Disposition Following Parent and Prodrug Administration in Mice

Brain delivery of active anti-HIV compounds is important for successful treatment of the AIDS patient. As an initial step in predicting human brain drug concentrations, hybrid pharmacokinetic models were developed to characterize the disposition of anti-HIV nucleosides following parent and prodrug administrations in mice. Mouse data were obtained following intravenous administration of 3-azido-2,3-dideoxyuridine (AZddU or AZDU), 3-azido-3-deoxythymidine (AZT), and their dihydropyridine prodrugs (AZddU-DHP and AZT-DHP). Exponential equations were fitted to the serum concentration–time data for each species, including the pyridinium ion moieties, and subsequently used in differential mass balance equations describing the brain dynamics of each compound. Model parameters for the mass balance equations were estimated by various techniques, including the utilization of in vitro data. In general, model-predicted brain concentrations agreed with the observed data. Similar data in larger animals will permit scale-up of the current model to predict human brain drug concentrations.     

Transoesophageal echocardiogram may fail to diagnose peri-operative myocardial infarction

We report a case in which a 55-yr-old man undergoing aortocoronary bypass was monitored with electrocardiogram and transoesophageal echocardiogram. Intraoperative electrocardiogram and simultaneous ECG recordings using the Holter monitor showed an ST elevation of greater than 2 mm and new Q wave formation in leads AVF and V5 during skin closure. However, the transoesophageal echocardiogram showed no wall motion abnormalities. No significant haemodynamic abnormalities were observed during the period of intraoperative ECG changes. He was treated with nitroglycerin infusion. Confirmation of a perioperative myocardial infarct was documented by postoperative 12-lead ECG and CPK-MB. A post-operative transthoracic echocardiogram showed a hypokinetic left ventricle with an anteroapical infarct. Thus transoesophageal echocardiography failed to detect an apical wall motion abnormality when the probe was placed at the midpapillary level. This limitation can be overcome by periodically obtaining apical views or by using probes with more than one imaging plane.     

Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines

BACKGROUND: A number of recent studies have identified interleukin (IL)-6 as an important regulator of prostate cancer growth. Here, we investigate the potential interaction of IL-6 with phosphatidylinositol (PI)-3 kinase, a key growth regulatory enzyme, in prostate cancer cell lines. METHODS: Tyrosine phosphorylation of p85, the regulatory subunit of PI-3 kinase, in the human prostate cancer cell lines LNCaP and PC-3 was assessed by sequential immunoprecipitation with anti-p85 antibody and immunoblotting with anti-phosphotyrosine. The effects of wortmannin, an inhibitor of PI-3 kinase, and/or IL-6 on cell growth were assessed by MTT assays. DNA laddering experiments were performed to assay for programmed cell death. RESULTS: Tyrosine phosphorylation of p85 is upregulated by IL-6 in both LNCaP and PC-3. IL-6 promotes coprecipitation of p85 with gp130, the signal-transducing component of the IL-6 receptor. Inhibition of PI-3 kinase with wortmannin induces programmed cell death in PC-3 cells. In contrast, wortmannin has no effect on LNCaP growth when used alone; however, combined with IL-6, wortmannin promotes apoptosis in these cells. CONCLUSIONS: PI-3 kinase is involved in IL-6 signal transduction and delivers an antiapoptotic signal in human prostate cancer cell lines.     

Synchronous coexpression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival.

PURPOSE: To evaluate the potential of the new prognostic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in cervical cancer patients. EXPERIMENTAL DESIGN: Sixty-eight patients with International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who underwent concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraffin-embedded sections: (a). the EGFR-negative/COX-2-negative group (n = 11); (b). the EGFR-negative/COX-2-positive group (n = 8); (c). the EGFR-positive/COX-2-negative group (n = 27); and (d). the EGFR-positive/COX-2-positive group (n = 22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared. RESULTS: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found between the levels of EGFR and COX-2 immunopositivity (R(2) = 0.05, P = 0.07). Patients in the EGFR-positive/COX-2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P = 0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P = 0.05, log-rank test). In addition, the synchronous coexpression of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multivariate analyses (relative risk = 4.0, P = 0.03). CONCLUSIONS: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactivity may be used as a potent molecular risk factor for predicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix.     

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral, selectively tumor-activated fluoropyrimidine with proven activity in the treatment of advanced colorectal cancer. This trial was conducted to evaluate the efficacy, safety and feasibility of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer, with a view to replacing 5-fluorouracil (5-FU) in such patients. PATIENTS AND METHODS: Forty-four patients received capecitabine 1250 mg/m2 twice daily (2500 mg/m2/day) for 14 days followed by 7 days of rest, for up to six cycles. RESULTS: Capecitabine produced an objective response rate of 34% (all partial responses) and stable disease in 14 patients (30%). The median time to disease progression (TTP) was 3.2 months [95% confidence interval (CI) 2.7-6.4 months] and median overall survival was 9.5 months (95% CI 6.9-13.2 months). Hand-foot syndrome (HFS), nausea, anorexia, diarrhea and vomiting were the most common adverse events. While HFS was the most frequent grade 3/4 toxicity (National Cancer Institute Common Toxicity Criteria), only 9% of patients experienced grade 3 HFS. Severe myelosuppression was not reported during the study. CONCLUSIONS: Capecitabine monotherapy is active and well tolerated as first-line therapy in patients with advanced/metastatic gastric cancer. Larger comparative trials investigating capecitabine-based combination regimens in patients with advanced gastric cancer are warranted.     

Use of the anterior interbody fresh-frozen femoral head allograft in circumferential lumbar fusions

Many studies in the literature have documented the outcome of circumferential lumbar fusions. However, no study has specifically evaluated the performance of the anterior fresh-frozen femoral head allograft as a structural interbody graft material. All office and hospital records, including charts and radiographs, were reviewed to obtain pertinent clinical and radiographic information. The cases included 23 single-level fusions, 22 two-level fusions, and 5 fusions of three or more levels. In all, 88 fusion levels were analyzed radiographically. The mean follow-up time was 28 months (range, 24 to 36 months). All procedures were performed in a single stage. At the latest follow-up, clinical outcome was graded good to excellent in 39 (78%) cases, fair in 8 (16%) cases, and poor in 3 (6%) cases. The average time to anterior radiographic fusion was 6 months (range, 4 to 8 months). The overall fusion rate was 98%. The average preoperative anterior disk space height was 10 mm, 14 mm immediately after operation, and 13 mm at follow-up. The posterior disk space height averaged 5 mm before operation, 7 mm immediately after operation, and 6 mm at follow-up. The average segmental lordosis was 7 degrees before operation, 10 degrees immediately after operation, and 10 degrees at follow-up. Late postoperative disk space collapse of 3 mm or more was noted in 17% of the fused disk spaces examined. Seventy-eight percent of the disk spaces maintained a disk space height greater than that of their preoperative value at the latest follow-up. Segmental lordosis did not change significantly at follow-up. The occurrence of collapse did not correlate with the clinical result, smoking history, or surgical indication (p < 0.05). Perioperative complications included one pleural effusion, two urinary tract infections, and one deep wound infection. Late complications included five painful graft sites and two patients with pseudarthrosis. Fresh-frozen femoral head allograft fulfills its desired function as an anterior structural graft in combination with rigid posterior transpedicular fixation, maintaining the disk space height achieved at surgery while reliably allowing remodeling and incorporation into a solid anterior fusion.