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P-280 NAVELBINE IN THE TREATMENT OF METASTATIC GASTRIC CANCER Zhavrid E, Sachivko N & Khodina T Institute of Oncology and Medical Radiology, Minsk, Belarus The choice of treatment options for metastatic gastric cancer is limited, which stimulates the search for new cytostatic agents potentially active against this disease. The objective of this study was to assess the feasibility of navelbine administration in the treatment of metastatic gastric cancer. Materials and methods: From January 2003 through November 2005, fifty-three primary patients with metastatic gastric cancer were randomized to receive chemotherapy with or without navelbine. Group 1 25 patients ; were treated with continuous infusion of fluorouracil 1000 mg m2 d for 72 h, methotrexate 40 mg m2 i.v. bolus day 1, leucovorin 200 mg m2 i.v. for 2 h days 2 and 3. Group 2 28 patients ; received the same regimen supplemented with navelbine 25 mg m2 i.v. for 1015 min, days 1 and 5. The interval between the courses was 3 weeks. The average number of chemotherapy courses in group 1 was 3.8 range 27 ; , in group 24.6 210 ; . The mean age of group 1 patients was 56 years range 2467 ; , of group 259 years range 3871 ; . The performance status of the patients in the both groups was 01 according to the ECOG scale. Results: The results of the treatment were evaluated in all the patients. Complete response occurred in no case. In group 1, partial response was observed in 2 8% ; patients 95% confidence interval CI ; : 2.513.5 ; , stable diseasein 11 44% ; patients CI: 33.954.1 ; , progressionin 12 48% ; patients CI: 37.858.2 ; . In group 2, partial response was registered in 6 21.4% ; patients CI: 13.529.3 ; , stable diseasein 13 46.4% ; patients CI: 36.856.0 ; , progressionin 9 32.1% ; patients CI: 23.141.1 ; . The median time before disease progression was 5.4 months in group 1 and 7.1 months in group 2. Supplementation with navelbine did not increase the treatment toxicity. Conclusion: The data obtained suggest that navelbine is potentially active against gastric cancer.
Pole in alternating periods when each experiences its winter and lower temperatures lead to more methane rain, Wall says. Ethane in the atmosphere also seems to get channeled towards the poles. Ethane rain might fall preferentially at the poles as a result, says radar team member Ralph Lorenz of the Johns Hopkins Applied Physics Laboratory in Laurel, Maryland, US. "Either or both effects may be contributing to the apparent preference of lakes to be near the poles, " Lorenz told New Scientist.

Sabine Knig & Ingo Heilmann1 Department of Plant Biochemistry, Albrecht-von-Haller-Institute for Plant Sciences, Georg-August-Universitt Gttingen, Justus-von-Liebig-Weg 11, 37077 Gttingen, Germany 1 To whom correspondence should be addressed email iheilma uni-goettingen ; Abstract Phosphoinositide microdomains within a membrane impart specificity to signaling pathways by recruiting and regulating target proteins that mediate cellular processes during development or stress conditions. Using the unicellular red alga Galdieria sulphuraria as a model system, the presence of a distinct plasma membrane pool of phosphoinositides was established that changes dynamically over the culture period of the alga. Other phosphoinositide pools may be localized in endomembranes, the nucleus, or the cytoskeleton, and such compartmentation may help to control regulatory phosphoinositide-protein interactions. Here we asked whether molecular phosphoinositide species in different pools would diverge in their associated fatty acid moieties, indicating variations in biogenesis. G. sulphuraria cells were harvested at various time points of the culture period. Individual phospholipids were isolated and their molecular compositions analyzed by gas chromatography and mass spectrometry. The results indicate dynamic changes in plasma membrane phosphoinositide molecular species over time that may reflect pool rearrangement and transient membrane processes, e.g. when cells enter the stationary phase. Preliminary results with Arabidopsis plants support the hypothesis of independently maintained subcellular lipid pools and may indicate a role for phosphoinositide fatty acyl moieties in maintaining the subcellular organization of these lipids. Introduction Phosphoinositide regulation of eukaryotic cellular processes involves the interaction of the lipids with protein partners that may be recruited to target membranes or become modified in their biochemical activity by the lipid ligands Stevenson et al., 2000; Meijer and Munnik, 2003; Balla, 2006; Santarius et al., 2006 ; . Examples of target proteins regulated by phosphoinositides include ion-channels and ATPases Cote et al., 1996; Hilgemann et al., 2001; Suh and Hille, 2005 ; , and proteins controlling actin dynamics Lemmon et al., 2002; Doughman et al., 2003; Wasteneys and Galway, 2003; Wenk and De Camilli, 2004 ; or vesicle trafficking Roth, 1999, 2004 ; . Obviously, phosphoinositide-protein interactions must be tightly regulated; however, it is currently unclear how interactions of multifunctional phosphoinositides with alternative partners are coordinated in order to avoid conflicting physiological effects. In a previous study the presence of independent subcellular pools of phosphatidylinositol 4, 5-bisphosphate [PtdIns 4, 5 ; P2] was demonstrated in the unicellular red alga Galdieria sulphuraria Heilmann et al., 1999; Heilmann et al., 2001 ; . It is our hypothesis that compartmentation restricts phosphoinositide-protein interactions according to physiological requirements Fig. 1 ; , and that individual phosphoinositide pools are comprised of molecular species differing in their fatty acyl moieties. In this scenario both the inositolphosphate headgroup and the fatty acyl moiety of an inositol lipid may be of consequence for its subcellular distribution and physiological role. In support of this idea, recombinant human phosphoinositide phosphatases have been shown to exhibit preferences for both certain phosphoinositide headgroup species and for species with certain fatty acid moieties in vitro Schmid et al., 2004 ; . This and other examples Heilmann et al., 2004 ; show that lipid-modifying enzymes can have preferences for both the headgroup and the fatty acyl moiety of a lipid substrate and are, thus, capable of recognizing either property of a lipid molecule. So far, studies of phosphoinositide 292 and albendazole. Leucovorin reduced form of folic acid ; is commonly used to rescue cells exposed to folate antagonists i.e., methotrexate ; - does not function as a cytotoxic chemotherapy agent.

Completed their business dealings successfully. "I wonder what Moshe'le is up to, " he thought of his young son. "He can probably say a few words by now. And Shmerel, no doubt, has made progress and has begun learning Mishnayos in school. And Chana'le." He stopped in horror and looked about. "Who screamed? Where I?" He jumped up in terror and looked all around and realized that this wasn't a dream. He had been daydreaming about his children, but here in the forest, stood three menacing characters brandishing knives. One of them called out to him to get down from the coach, as he waved his knife threateningly. It finally sank in; Shaul was being held up by robbers. One of the three approached him and Shaul put up his hands helplessly. They made a quick search of Shaul's clothes and belongings while one of them pushed Shaul into the mud. His hands and feet were tied to the trunk of a tree, and Shaul began to realize that his end was nigh. He looked about him in desperation but help was nowhere to be found. There was only the forest, the robbers, and himself. One of the men came over to him and snarled, "Prepare to die." Trembling in fright, Shaul tried to focus on his final Vidui. "These are my final moments, " he thought resignedly. Images of his parents were clear in his mind's eye, as were his dear wife Sarah'le and the sweet faces of his children. His eyes filled with tears as he thought of leaving everything he cherished behind. Thoughts of the past continued to flit by: the beis midrash of his Rebbe.an eight-year-old child himself sitting on his father's lap.his father whispering to him to sing. Shaul opened his eyes and faced. Subject protocol Patients were selected according to the American Rheumatism Association 1987 classification criteria 20 ; . The group consisted of 16 patients with RA 12 female and 4 male ; who ranged in age from 23 to 76 years, with a mean age of 48.6 15 ; . 15 patients were taking nonsteroidal antiinflammatory drugs NSAIDs ; and 1 patient was untreated. In addition, patients were taking disease modifying antirheumatic drugs and or glucocorticoids 3 hydroxychloroquine, 3 oral methotrexate, 3 hydroxychloroquine oral methotrexate, 1 hydroxychloroquine prednisone, 1 hydroxychloroquine prednisone oral methotrexate, 1 cortisone, 2 Azulfidine, 1 Azulfidine methotrexate ; . Sex and age-matched healthy controls were recruited. Controls were free of chronic pain, cardiovascular complaints, or other chronic inflammatory diseases. Sample preparation PBMC were isolated from heparin anticoagulated whole blood by Ficoll-Isopaque Pharmacia, Uppsala, Sweden ; density gradients 21 ; . For preparation of cytosolic fractions, PBMC were lysed in ice-cold lysis buffer 10 mM Tris, 5 mM EDTA, 7.5 mM mgCl2, 0.1 mM PMSF, 10 g ml leupeptin, 5 g ml pepstatin, 10 g ml benzamidine, at pH 7.4 ; , using a polytron tissue disrupter Janke and Kundel, Staufen, Germany ; at low speed for 40 s on ice. Unbroken cells and nuclei were pelleted by centrifugation 800 g for 5 min ; and discarded. The supernatant was then centrifuged 48, 000 g for 20 min at 4C ; to separate plasma membrane from the cytosol. The latter was centrifuged at 300, 000 g for 30 min at 4C. The supernatant was collected and frozen in liquid nitrogen. Membrane preparation was washed once in cell lysis buffer and recentrifuged at 48, 000 g for 20 min at 4C; the resultant membrane pellet was resuspended in cell lysis buffer and sonicated for 5 s before protein determination. In addition to assay membrane-associated GRK activity, membranes were washed once in cell lysis buffer, centrifuged at 48, 000 g for 20 min at 4C, and the resultant membrane pellet was resuspended in cell lysis buffer with 250 mM NaCl to detach membrane-bound GRKs ; 22 ; . The suspension was sonicated briefly, incubated for 30 min at 4C and centrifuged as above. Membrane-detached proteins 25 g ; were used in the phosphorylation assay. Protein concentration was determined with a Bio-Rad protein assay reagent, using bovine serum albumin as standard. Assessment of G-protein-coupled receptor kinase activity GRK enzymatic activity was assessed using light-dependent phosphorylation of rhodopsin 23 ; . We purified rod outer segment membranes ROS ; from dark-adapted bovine retinas by stepwise sucrose gradient centrifugation and subseLOMBARDI ET AL and trileptal. The respiratory rates of normal and neoplastic cerebral tissues, and the effect of various anticancer drugs upon them, were measured according to the standard in vitro Warburg technic. The temporal and parietal lobes of normal brain had higher respiratory rates than did the occipital and frontal lobes, and gray matter had a much higher respiratory rate than white matter. Primary and metastatic brain tumors had respiratory rates similar to normal white matter, the degree of malignancy of brain tumors being inversely proportional to the respiratory rate. The respiration of normal brain tissue was usually inhibited by each anticancer drug, whereas the response of brain tumors was variable. Of particular interest was the stimulatory effect of A139 and methotrexate upon the respiration of certain tumors. 3. Drug-related criteria that most affect the selection and antabuse.

Autologous Transplantation for Breast Cancer survival 8.5 months. Patients entered into the phase I II HDC trials of dose intensification often had failed such salvage. The phase I HDC data indicated that the frequency of objective response was significantly higher approximately 70% ; than observed with SDC salvage regimens [75-77]. Indeed, complete responses were observed in 17% to 37% of patients. The objective response rate to HDC was 2 to 10 times greater than for SDC, even though SDC patients had received less prior chemotherapy. However, as with SDC in advanced disease, durable remissions were rare. Phase II trials of HDC without induction therapy established that long-term DFS could be produced in a percentage of patients. In updated data from Peters and coworkers [78], 3 of 22 14% ; poor-prognosis premenopausal patients who were estrogen receptor-negative, and had visceral dominant disease remain continuously disease-free at full performance status with minimum follow-up of 11 years and lead follow-up at 14 years. Consistent with the third of Skipper's rules, bulky metastatic disease might limit efficacy of HDC. Consequently the strategy of employing induction chemotherapy to reduce tumor burden prior to HDC and PBPCT was evaluated. While induction therapy appears to increase the complete response rate and to prolong the relapse-free interval, long-term DFS rate appears to be on the order of 20% to 30% with or without an induction regimen [4]. The favorable initial results of HDC prompted several groups to treat patients with this approach at relapse after therapy for primary disease. Patients in these series generally were young, premenopausal women, who were initially estrogen receptor-negative or hormone manipulation-refractory and who had measurable visceral disease. In contra-distinction to many SDC trials, prior adjuvant chemotherapy was usually permitted. A large number of such phase II HDC studies have now been reported [79-99]. The data in aggregate suggest that a single course of HDC will result in complete responses 30%-50% of the time and overall responses in approximately 80% of patients with metastatic breast cancer. ABMTR reported outcomes for HDC in metastatic disease are consistent with the reported phase II data [43]. There are now four available randomized studies in metastatic breast cancer. Two, including the study by Peters and his colleagues [100] the adriamycin fluouracine methotrexate [AFM] randomized trial ; and the study from Bezwoda and his coworkers [101] from South Africa, have been presented previously at ASCO. Both demonstrated improvement in EFS for patients receiving high-dose therapy compared to standard dose therapy alone South African study ; or as consolidation after an intensive standard therapy AFM randomized trial ; . There were two studies presented at the 1999 ASCO meeting which bear on the analysis of high-dose therapy in metastatic disease. The summary data and the previously reported randomized studies are summarized in Table 2.

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