Growth suppression of human colorectal carcinoma in nude mice by monoclonal antibody C27-abrin A chain conjugate

PURPOSE: The aim of this study was to assess an immunotoxin, monoclonal antibody C27-abrin A chain conjugate (MAAC), that might be effective in the treatment of colorectal carcinoma. METHODS: The immunotoxin was prepared by a specific monoclonal antibody against carcinoembryonic antigen (CEA), monoclonal antibody C27, linked toN-succinimidyl-3-(2-pyridyldithio)propionate and then coupled covalently to the toxic abrin-A chain to synthesize MAAC. The therapeutic role of this immunotoxin in suppressing thein vitro andin vivo growth of CEA-secreting human colorectal cancer cells (LS174T) was assayed by methods of protein biosynthesis inhibition, cell colony proliferation, and treatment of tumor cells before and after inoculation in nude mice. RESULTS: We found that MAAC effectively suppressed the growth of LS174T in culture medium and completely eradicated cells in inoculated nude mice. In contrast, irrelevant immunotoxin antiferritin-abrin A chain conjugate and isotype-matched monoclonal immunoglobin (MOPC21IgG1)-abrin A chain conjugate did not cause such effects. Thein vitro toxicity was highly specific because the conjugate (MAAC) inhibitedde novo protein biosynthesis, impeded growth, and caused death of cells possessing surface CEA determinants. The 50 percent inhibition dose values of the conjugate for colonogenic survival and for protein biosynthesis in LS174T cells were 0.09 g/ml and 0.06 g/ml, respectively. Colony survival was inhibited 96.3 percent after prolonged MAAC treatment. MAAC showed selective cytotoxicity; the inhibitory effect of MAAC to the CEA-secreting LS174T cells over the CEA-nonsecreting human embryonic kidney cells was 16-fold. CONCLUSION: These results indicate that MAAC may be of benefit in therapy during or soon after resection of colorectal carcinoma or in patients who have micrometastasis.Supported by a grant from the National Science Council and the Veterans General Hospital-Taipei, Taipei, Taiwan.     

Differential regulation of EGF production, EGF receptor-binding, and cellular growth by sodium-butyrate in hep3b and plc/prf/5 human hepatoma-cells

Hep3B and PLC/PRF/5 human hepatoma cells express epidermal growth factor (ECF) mRNA and secret this polypeptide growth factor into the culture medium. The production of EGF was inhibited by sodium butyrate in a dose-dependent manner. EGF receptor numbers in both cell lines were increased after treatment with butyrate for 2 days, In addition, the binding affinity of EGF to its receptor was decreased in butyrate-treated PLC/PRF/5 cells while it did not change in Hep3B cells. EGF-stimulated cell growth in PLC/PRF/5 cells was attenuated by sodium butyrate whereas no significant inhibition df cell growth of Hep3B cells was found in the same condition. Our results suggest that EGF acts as an autocrine growth stimulator in human hepatoma cells and sodium butyrate can differentially regulate the responses of hepatoma cells to EGF by modulating the differentiation states of these cells.     

Rectal cancer mortality and total hardness levels in Taiwan's drinking water.

The possible association between the risk of rectal cancer and hardness levels in drinking water from municipal supplies was investigated in a matched case-control study in Taiwan. All eligible rectal cancer deaths (986 cases) of Taiwan residents from 1990 through 1994 were compared with deaths from other causes (986 controls), and the hardness levels of the drinking water used by these residents were determined. Data on water hardness throughout Taiwan were collected from Taiwan Water Supply Corporation (TWSC). The control group consisted of people who died from other causes and the controls were pair matched to the cases by sex, year of birth, and year of death. The results show a significant negative relationship between drinking water hardness and rectal cancer mortality. Odds ratio and 95% confidence intervals were 1.24 (1.01-1. 55) and 1.38 (1.10-1.73), respectively, for exposure to moderately hard water and soft water compared with the use of hard water. Trend analyses showed an increasing odds ratio for rectal cancer with decreasing levels of hardness in drinking water. This is an important finding for the Taiwan water industry and human health.     

Sensible approaches to avoid needle stick accidents in nuclear medicine

OBJECTIVE: Needle sticks are a continuous concern in the health care environment because of the prevalence of bloodborne pathogens in today's society. Radioactive contamination is another concern with needle sticks during nuclear medicine and nuclear pharmacy procedures. In our institution, substantial efforts have been made to prevent needle sticks, but they still occur occasionally. The purpose of this project was to analyze different practices and products to determine the best protocol in an effort to avoid further needle sticks. METHODS: The nuclear medicine technologists were surveyed to determine how many needle sticks have occurred and the situation behind each occurrence. Using our initial survey, the circumstances involved in each incident were reviewed, suggestions considered, and various means of protection analyzed. Five options were presented in a second survey. RESULTS: The results of the second survey showed that technologists favored the newly designed needle-capping blocks for preventing needle sticks in their daily routine procedures. CONCLUSION: The newly designed needle-capping block is best suited for both nuclear medicine and nuclear pharmacy laboratories. We will continue to monitor the effectiveness of this new approach in preventing needle sticks.     

Comparison of flomoxef with latamoxef in the treatment of sepsis and/or Gram-negative bacteremia in adult patients

The safety and efficacy of flomoxef and latamoxef were compared in the treatment of hospitalized patients with sepsis and/or Gram-negative bacteremia in a prospective, open-labelled clinical trial. Patients were randomized to receive 1 to 2 g intravenous doses of either flomoxef every 6 to 12 h, or latamoxef every 8 to 12 h. Data from 21 patients given flomoxef and 23 patients given latamoxef were included in the evaluation of efficacy. Flomoxef produced clinical cure and satisfactory microbiological responses in 85.7% and 100% of patients, respectively. These results were similar to those obtained with latamoxef (87% and 100%, respectively). In addition, no significant difference was found in mean age, sex, severity of infection, distribution of pathogens and focus of infection between the two groups. However, the flomoxef group included more patients with ultimately fatal diseases. Six patients given flomoxef and two patients given latamoxef developed superinfections caused by yeast, enterococci and Pseudomonas aeruginosa in the urinary tract. Mild and reversible adverse reactions probably related to flomoxef and latamoxef were noted in 14.3% and 13% of patients, respectively. The results of this study demonstrated that flomoxef is a safe and effective antimicrobial agent in the treatment of patients with sepsis and/or Gram-negative bacteremia.     

Growth suppression of low HER-2/neu-expressing breast cancer cell line MDA-MB-435 by tyrosine kinase inhibitor emodin

The tyrosine kinase inhibitor emodin (3-methyl-1,6,8-tridroxyanthaquinone) is known to preferentially suppress the growth of the HER-2/neu-overexpressing breast cancer cell line. In this study, emodin effectively suppressed growth of MDA-MB-435, a breast cancer cell line with low HER-2/neu expression. Since emodin is a tyrosine kinase inhibitor, we questioned whether another tyrosine kinase might play a role in the tumorigenicity of MDA-MB-435. By Western blotting with anti-phosphotyrosine antibody, we detected a 72-kDa protein which is uniquely phosphorylated on tyrosine in MDA-MB-435. The level of phosphotyrosine in the 72-kDa protein was significantly reduced by treatment with emodin. This suggests that a strong tyrosine kinase may reside in MDA-MB-435 and the 72-kDa protein serves as a substrate for the tyrosine kinase.     

Comparative absorption kinetics of intramuscular midazolam and diazepam

Purpose

This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam.

Methods

Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution.

Results

There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volumes and clearances) of intravenous midazolam and diazepam. The mean (±sd) time to peak plasma concentration (C_max) was shorter for im midazolam (17.5 ± 6.5 min) relative to diazepam (33.8 ± 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 ± 2 vs 13.8 ± 7.5 min). The peak rate of absorption was identical (0.18 mg · min^?1) and bioavailability was 1.0 for both drugs.

Conclusions

We conclude that midazolam has more rapid absorption than diazepam following im administration.     

Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder characterized by degeneration of large motor neurons of the brain and spinal cord. A subset of ALS is inherited (familial ALS, FALS) and is associated with more than 70 different mutations in the SOD1 gene. Here we report that lymphoblast cell lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) compared with sporadic ALS (SALS) and normal controls (spouses of ALS patients). The ROS generation did not correlate with SOD1 activity. Further, cells incubated with vitamin C, catalase or the flavinoid quercetin significantly reduced ROS in all groups. The catalase inhibitor 3-amino-1,2,4-triazole resulted in a ten-fold increase of ROS in all groups. Neither L-nitroarginine, a nitric oxide synthase inhibitor or vitamin E altered the ROS levels. Thus, these studies suggest that hydrogen peroxide (H(2)O(2)) is a major ROS elevated in FALS lymphoblasts and it may contribute to the degeneration of susceptible cells. Further, we postulate a mechanism by which increased H(2)O(2) could be generated by mutant SOD1.     

The surgical treatment for degenerative disease of the ankle

Although a variety of surgical techniques are available for the surgical treatment of early degenerative disease of the ankle, arthrodesis remains the preferred treatment for severe cases. We studied 126 ankles with an average follow up of 39 months of whom 25 with early disease underwent debridement and cheilectomy, 18 with intermediate disease underwent lower tibial osteotomy and 83 with severe disease underwent either arthrodesis (78) or total ankle replacement (5). In 96% of cases there was a satisfactory functional outcome.