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Locoregional recurrence is the most common complication after adenocarcinoma resection in the colon, despite adjuvant chemotherapy. Therapy efficacy could be improved if designed to target malignant cells by incorporating specific recognition factors in the drugs or the drug vehicles. The aim of this study was to elucidate whether the overexpression of sialic acid (SA) on colonic malignant tissues could be utilized for drug targeting by cationic polymers.Cell lines (IEC-6, SW-480 and SW-620) and colon polyps and normal adjacent tissues harvested from dimethylhydrazine (DMH) induced rats were used as in vitro and in vivo models of different metastatic stages of colon cancer. SA expression was identified by fluorescent wheat germ agglutinin (WGA), and verified by pretreatment with neuraminidase. The role of mucus in the mucosal binding experiments was explored by pretreatment with dithiothreitol (DTT). The binding of FITC labeled cationic polymers of various degrees of cationization to normal and malignant colonic cells and tissue was measured.SA was overexpressed on malignant colonic cells and tissues, and its expression correlated to the metastatic stage in vitro. The binding of the cationic copolymers to the cell lines and tissues correlated with the charge density of the polymer and with the metastatic stage of the cell line. The interaction between the malignant colonic cells and tissues with the polymers was SA dependent and increased after mucus removal.Cationic polymers could be used as a targeting tool to colonic malignant epithelium, to be implemented in drug delivery and diagnosis.

Cell lines that do not overexpress functional cyclooxygenase-2 are resistant to the normal plasma levels of celecoxib achieved following oral ingestion. Cell growth inhibition was demonstrated after 24 h exposure to 80 micromol/l celecoxib while significant death was not detected at concentrations below 120 micromol/l following 24 h exposure. This growth inhibition and death induction was identified to be independent of p53 and Hdm2 in these cells, despite wild-type p53 stabilization and Hdm2 diminution in some lines. Cell death induced by celecoxib was preceded by the generation of reactive oxygen species within 4 h of drug exposure. The precise mechanism of elicitation of reactive oxygen species in these cells remains to be elucidated, although it was found to be independent of p53 and c-Abl, while in vitro, celecoxib enhanced superoxide radical production by xanthine oxidase. Importantly, the failure of anti-oxidants to protect from death indicates that celecoxib induces death independently of reactive oxygen species and that reactive oxygen species generation may be an insufficient trigger of death in p53-deficient cells.

The purpose of this study was to develop a biodegradable drug platform composed of chitosan and guar gum and to explore the possibility of using it for local adjuvant or neoadjuvant therapy of colorectal cancer. Celecoxib (Cx), a chemopreventative drug for familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal malignancies, was selected as a model drug for this topical system because of the contraindications that are associated with its systemic administration. Films made of chitosan (Ct) and guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of cancer cells directly, while chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable polysaccharide composites.

In December 1995, ambient radon levels exceeding 10,000 Bq/m3 were measured in a basement shelter workroom of a multilevel East Talpiot, Jerusalem, public elementary school (six grades, 600 students). The measurements were taken after cancers (breast and multiple myeloma) were diagnosed in two workers who spent their workdays in basement rooms. The school was located on a hill that geologic maps show to be rich in phosphate deposits, which are a recognized source for radon gas and its daughter products. Levels exceeding 1000,000 Bq/m3 were measured at the mouth of a pipe in the basement shelter workroom, the major point of radon entry. The school was closed and charcoal and electret ion chamber detectors were used to carry out repeated 5-day measurements in all rooms in the multilevel building over a period of several months. Radon concentrations were generally higher in rooms in the four levels of the building that were below ground level. There were some ground-level rooms in the building in which levels reached up to 1300 Bq/m3. In rooms above ground level, however, peak levels did not exceed 300 Bq/m3. Exposure control based on sealing and positive pressure ventilation was inadequate. These findings suggested that radon diffused from highly contaminated basement and ground-floor rooms to other areas of the building and that sealing off the source may have led to reaccumulation of radon beneath the building. Later, subslab venting of below-ground radon pockets to the outside air was followed by more sustained reductions in indoor radon levels to levels below 75 Bq/m3. Even so, radon accumulated in certain rooms when the building was closed. This sentinel episode called attention to the need for a national radon policy requiring threshold exposure levels for response and control. A uniform nationwide standard for school buildings below 75 Bq/m3 level was suggested after considering prudent avoidance, the controversies over risk assessment of prolonged low-level exposures in children, and the fact that exposures in most locations in the Talpiot school could be reduced below this level. Proposal of this stringent standard stimulated the search for a strategy of risk control and management based on control at the source. This strategy was more effective and probably more cost effective than one based on suppression of exposure based on sealing and ventilation. Because many Israeli areas and much of the West Bank area of the Palestinian National Authority sit on the same phosphate deposits, regional joint projects for surveillance and control may be indicated. Images Figure 1. Figure 2.