X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model.

Deregulation of apoptotic pathways plays a central role in cancer pathogenesis. X-linked inhibitor of apoptosis protein (XIAP), is an antiapoptotic molecule, whose elevated expression has been observed in tumor specimens from patients with prostate carcinoma. Studies in human cancer cell culture models and xenograft tumor models have demonstrated that loss of XIAP sensitizes cancer cells to apoptotic stimuli and abrogates tumor growth. In view of these findings, XIAP represents an attractive antiapoptotic therapeutic target for prostate cancer. To examine the role of XIAP in an immunocompetent mouse cancer model, we have generated transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that lack XIAP. We did not observe a protective effect of Xiap deficiency in TRAMP mice as measured by tumor onset and overall survival. In fact, there was an unexpected trend toward more aggressive disease in the Xiap-deficient mice. These findings suggest that alternative mechanisms of apoptosis resistance are playing a significant oncogenic role in the setting of Xiap deficiency. Our study has implications for XIAP-targeting therapies currently in development. Greater understanding of these mechanisms will aid in combating resistance to XIAP-targeting treatment, in addition to optimizing selection of patients who are most likely to respond to such treatment.

Simple new method for effective concentration of 188Re solutions from alumina-based 188W-188Re generator.

UNLABELLED: (188)Re is a useful generator-produced radioisotope currently under evaluation for a variety of therapeutic applications, including bone pain palliation and intravascular radiation therapy. Because the (188)W parent is available only in a relatively low specific activity (<0.15-0.19 GBq/mg) from reactor irradiation of enriched (186)W, relatively large volumes of 0.9% saline (>15 mL) are required for elution of the (188)Re daughter from traditional alumina-based (188)W-(188)Re generators. Because these large bolus volumes result in solutions with a relatively low specific volume activity of (188)Re (<1 GBq/mL for the 18.5-GBq generator), the availability of effective methods for eluent concentration is important. Our new approach is based on the use of 0.3 mol/L ammonium acetate as a representative salt of a weak acid instead of saline for generator elution. METHODS: After generator elution, the ammonium acetate generator eluent (15-20 mL) is passed through a tandem IC-H Plus cation (Dowex-H)-anion (QMA Light) column system. Exchange of ammonium cations with hydrogen ions on the cation column forms an acetic acid solution containing perrhenate anions from which the macroscopic levels of the acetate anion of the eluent have been effectively removed. Because perrhenic acid is fully dissociated at this pH, the QMA Light column specifically traps the (188)Re-perrhenate, which is subsequently eluted with a low volume (<1 mL) of saline. Concentration ratios greater than 20:1 are readily achieved with this method. RESULTS: A typical clinical-scale generator loaded with 19.2 GBq (188)W was used to validate the approach. Saline elution provided (188)Re in a 75%-80% yield. Although elution with 0.15 mol/L NH4OAc gave lower yields (55%-60%), use of 0.3 mol/L NH4OAc provided yields comparable with those of saline (70%-75%). (188)W parent breakthrough was not detected after passage of the bolus through the tandem concentration system. Bolus volumes of 15-20 mL, which initially contained as much as 11.1-14.8 GBq (188)Re, were readily concentrated to less than 1 mL saline using QMA Light cartridges. The generator was evaluated for more than 3 mo with no decrease in performance. CONCLUSION: This approach represents a simple, rapid, and effective method using inexpensive disposable components of concentrating solutions of (188)Re for preparation of therapeutic agents.

Levels of chlordane compounds in fish muscle, -meal, -oil and -feed.

Cis-, trans-, oxychlordane and trans-nonachlor were determined in the edible part of more than 140 fish samples of 15 different species and in fish meal, -oil and fish feed. The investigated fish included most of the important fish species consumed in Germany. Highest concentrations were found in muscle of marine fish with high or moderate fat content, but also in eel and farmed salmon. Marine fish with low fat content contained only traces of chlordane in the muscle tissue. A relationship between fishing ground and levels of chlordane could not be established. Contamination level of herring was related to the age (length) of the fish. Data are also given for contamination levels of fish meal, -oil and -feed.

Levels of toxaphene indicator compounds in fish meal, fish oil and fish feed.

Three toxaphene indicator compounds were determined in fish oil and fish meal of different origin and raw material as well as in feed containing fish oil and fish meal. Fish oil and fish meal from South America contained no or only traces of the indicator congeners. The sum of the three compounds varied in fish oils from Europe between 13 micrograms/kg fat (sand eel oil) and 206 micrograms/kg fat (cod oil). Varying concentrations were also determined in European fish meal and in feed. Toxaphene indicator compounds were as well detected in trout and salmon fed with toxaphene residues containing feed. Results indicate that feed can contribute to toxaphene contamination of farmed salmon from Europe.