Flowchart: Preparation: CEA
 
 
 
 

 D-G

 

 BC

 

  A

 
                    

                      

Text Box: CEA                                                                                      

 

Gastric Cancer                  

 

Text Box: IL8

Text Box: MIP-1alpha

Text Box: FZ33

                                                      

 

                                                                  

                                                                                       

Clin Cancer Res. 2006 Jun 15;12(12):3803-13.

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Carcinoembryonic Antigen-Targeted Selective Gene Therapy for Gastric Cancer through FZ33 Fiber-Modified Adenovirus Vectors.

Tanaka T, Huang J, Hirai S, Kuroki M, Kuroki M, Watanabe N, Tomihara K, Kato K, Hamada H.

Authors' Affiliations: Departments of Molecular Medicine and Clinical Laboratory Medicine, Sapporo Medical University, Sapporo, Japan and Departments of Surgery I and Biochemistry, School of Medicine, Fukuoka University, Fukuoka, Japan.

PURPOSE: A major problem when using the adenoviral vectors for gene therapy applications is thought to be related to low transduction efficiency in cancer cells or to side effects in normal cells. There is an urgent requirement to improve the specificity of gene delivery in the context of cancer gene therapy. EXPERIMENTAL DESIGN: We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33, within the HI loop (Adv-FZ33). A remarkable degree of targeted gene delivery to gastric cancer cells was obtained with Adv-FZ33 with the fully human anti-carcinoembryonic antigen (CEA) monoclonal antibody, C2-45. RESULTS: In vitro LacZ or EGFP gene expression after Adv-FZ33 infection via C2-45 was 20 times higher than control monoclonal antibody in MKN-45 at 1,000 viral particles/cell. We generated Ax3CAUP-FZ33 (UP-FZ33), which is an Adv-FZ33 derivative vector expressing a therapeutic gene (i.e., Escherichia coli uracil phosphoribosyltransferase), which converts 5-fluorouracil (5-FU) directly to 5-fluoro-UMP. UP-FZ33 with C2-45 enhanced the cytotoxicity of 5-FU by 10.5-fold in terms of IC(50) against MKN-45 compared with control IgG4. In a nude mouse peritoneal dissemination model, tumor growth in mice treated with UP-FZ33/C2-45/5-FU was significantly suppressed, and tumor volumes were less than one-fourth of those of the control IgG4 group (P < 0.05). The median survival time of the UP-FZ33/C2-45/5-FU group was significantly longer than those treated with PBS or 5-FU only (P < 0.01). CONCLUSIONS: These data suggest that CEA-targeted FZ33 mutant adenovirus-mediated gene delivery offers a strong and selective therapeutic modality against CEA-producing cancers.

PMID: 16778108 [PubMed - in process]

Dis Markers. 2006;22(3):103-9.

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Molecular detection of disseminated tumor cells in the peripheral blood of patients with gastric cancer: Evaluation of their prognostic significance.

Wu CH, Lin SR, Hsieh JS, Chen FM, Lu CY, Yu FJ, Cheng TL, Huang TJ, Huang SY, Wang JY.

MedicoGenomic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.

Early detection of disseminated tumor cells in the peripheral blood of patients with early stage gastric cancer could help to improve the outcome after tumor resection. The aim of this study is to evaluate the prognostic significance of tumor-related mRNA for the detection of circulating tumor cells in gastric cancer patients by a reverse-transcriptase polymerase chain reaction (RT-PCR) method. We simultaneously analyzed human telomerase reverse transcriptase (hTERT), cytokeratin-19 (CK-19), cytokeratin-20 (CK-20) and carcinoembryonic antigen (CEA) mRNA (messenger RNA) expression in the peripheral blood of 42 gastric cancer patients and 30 healthy individuals. Additionally, analyses were carried out for the correlation of these four molecular markers with patients' clinicopathologic features, as well as the occurrence of postoperative recurrence/metastasis. Among 42 gastric cancer patients, the prevalence of mRNA for hTERT, CK-19, CK-20, and CEA was 61.9% (26/42), 69% (29/42), 61.9% (26/42), and 78.6% (33/42), respectively. All 30 healthy individuals were negative for hTERT and CEA mRNA, while two were positive for either CK-19 mRNA or CK-20 mRNA. Positive CEA mRNA was significantly correlated with tumor size p=0.008), vessel invasion (p=0.001), depth of tumor invasion (p=0.007), lymph node metastasis (p< 0.001), and TNM stage (p<0.001). In addition, the multivariate logistic regression demonstrated that CEA mRNA expression was an independent and significant predictor for postoperative recurrence/metastasis (p=0.032). Our findings suggest that CEA mRNA may be a more reliable marker than hTERT, CK-19 and CK-20 for the detection of circulating cancer cells in gastric cancer patients' peripheral blood. Patients with positive CEA mRNA expression in peripheral blood have a significantly higher risk of postoperative recurrence/metastasis.

PMID: 16788243 [PubMed - in process]

 

Brain Behav Immun. 2006 Mar 28; [Epub ahead of print]

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Stress decreases, while central nucleus amygdala lesions increase, IL-8 and MIP-1alpha gene expression during tissue healing in non-human primates.

Kalin NH, Shelton SE, Engeland CG, Haraldsson HM, Marucha PT.

Department of Psychiatry, University of Wisconsin, Madison, WI 53719, USA; Department of Psychology, University of Wisconsin, Madison, WI 53719, USA.

Stress impairs healing and in part this effect is thought to be mediated by glucocorticoids. However, the brain systems that underlie the effects of stress on healing remain to be determined. Since the central nucleus of the amygdala (CeA) plays a role in mediating an individual's behavioral and physiological reactivity to stress, we investigated, in rhesus monkeys, whether selective lesions of the CeA altered the gene expression of chemokines (IL-8 and MIP-1alpha) that are associated with early dermal healing. We used rhesus monkeys because they provide an excellent animal model to investigate brain mechanisms relevant to human stress, anxiety, and psychopathology. Hypothalamic-pituitary-adrenal (HPA) activity was assessed in the monkeys prior to the wound healing experiment demonstrating that the CeA lesions reduce HPA activity. In the healing experiment, stress decreased IL-8 and MIP-1alpha gene expression in both CeA lesioned and non-lesioned animals. Conversely, the CeA lesions increased the tissue expression of IL-8 and MIP-1alpha mRNA prior to and after stress exposure. These results demonstrate that in primates the CeA is a key brain region involved in the regulation of processes associated with wound healing. Because of brain and behavioral similarities between rhesus monkeys and humans, these results are particularly relevant to understanding brain mechanisms that influence healing in humans.

PMID: 16574374 [PubMed - as supplied by publisher]