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Targeting Therapy (targeting + therapy)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2006
Christine L. Le Maitre
Summary Conventional therapies for low back pain (LBP) are purely symptomatic and do not target the cause of LBP, which in approximately 40% of cases is caused by degeneration of the intervertebral disc (DIVD). Targeting therapies to inhibit the process of degeneration would be a potentially valuable treatment for LBP. There is increasing evidence for a role for IL-1 in DIVD. A natural inhibitor of IL-1 exists, IL-1Ra, which would be an ideal molecular target for inhibiting IL-1-mediated effects involved in DIVD and LBP. In this study, the feasibility of ex vivo gene transfer of IL-1Ra to the IVD was investigated. Monolayer and alginate cultures of normal and degenerate human intervertebral disc (IVD) cells were infected with an adenoviral vector carrying the IL-1Ra gene (Ad-IL-1Ra) and protein production measured using an enzyme-linked immunosorbent assay. The ability of these infected cells to inhibit the effects of IL-1 was also investigated. In addition, normal and degenerate IVD cells infected with Ad-IL-1Ra were injected into degenerate disc tissue explants and IL-1Ra production in these discs was assessed. This demonstrated that both nucleus pulposus and annulus fibrosus cells infected with Ad-IL-1Ra produced elevated levels of IL-1Ra for prolonged time periods, and these infected cells were resistant to IL-1. When the infected cells were injected into disc explants, IL-1Ra protein expression was increased which was maintained for 2 weeks of investigation. This in vitro study has shown that the use of ex vivo gene transfer to degenerate disc tissue is a feasible therapy for the inhibition of IL-1-mediated events during disc degeneration. [source]

Aging Augments IL-17 T-Cell Alloimmune Responses

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009
B. M. Tesar
As increasing numbers of elderly patients require solid organ transplantation, the need to better understand how aging modifies alloimmune responses increases. Here, we examined whether aged mice exhibit augmented, donor-specific memory responses prior to transplantation. We found that elevated donor-specific IL-17, but not IFN-,, responses were observed in aged mice compared to young mice prior to transplantation. Further characterization of the heightened IL-17 alloimmune response with aging demonstrated that memory CD4+ T cells were required. Reduced IL-2 alloimmune responses with age contributed to the elevated IL-17 phenotype in vitro, and treatment with an anti-IL-17 antibody delayed the onset of acute allograft rejection. In conclusion, aging leads to augmented, donor-specific IL-17 immune responses that are important for the timing of acute allograft rejection in aged recipients. IL-17 targeting therapies may be useful for averting transplant rejection responses in older transplant recipients. [source]

Novel spliced form of a lens protein as a novel lung cancer antigen, Lengsin splicing variant 4

CANCER SCIENCE, Issue 8 2009
Munehide Nakatsugawa
A glutamine synthetase I family protein, Lengsin, was previously identified as a novel lens-specific transcript in the vertebrate eye. In this report, we show for the first time that Lengsin is a novel tumor-associated antigen expressed ectopically in lung cancer. Interestingly, a novel spliced form of human Lengsin termed ,splicing variant 4', gaining exon 3 that codes extra 63 amino acids, is the dominant transcript form in lung cancer cells. Lengsin mRNA could be detected in 7 of 12 (58%) lung cancer cell lines and 7 of 7 (100%) surgically resected lung cancer tissues. On the other hand, Lengsin transcripts could not be detected in normal major tissues or in other cancer cell lines, including melanoma, colorectal carcinoma, breast carcinoma and hepatocellular carcinoma. In addition, knockdown of Lengsin mRNA with RNAi caused cell death and a decrease of cell viability, suggesting that Lengsin has some essential role in cell survival. Since the lens is an immune-privileged site, we regard Lengsin as a highly immunogenic cancer antigen. Anti-Lengsin autoantibodies were detectable in sera of lung cancer patients, although these patients did not show any lens-related disturbances. Hence, Lengsin splicing variant 4 might be an immunogenic lung cancer-specific antigen that is suitable as a diagnostic marker and for molecular targeting therapy, including immunotherapy. (Cancer Sci 2009) [source]

Histone deacetylase inhibitors trichostatin A and valproic acid circumvent apoptosis in human leukemic cells expressing the RUNX1 chimera

CANCER SCIENCE, Issue 2 2008
Ko Sasaki
Disturbance of the normal functions of wild-type RUNX1 resulting from chromosomal translocations or gene mutations is one of the major molecular mechanisms in human leukemogenesis. RUNX1-related chimeras generated by the chromosomal translocations repress transcriptional activity of wild-type RUNX1 by recruiting the co-repressor/histone deacetylase complex. Thus, histone deacetylase inhibitors are expected to restore normal functions of wild-type RUNX1 and thereby affect the growth and differentiation ability of leukemic cells expressing the chimera. We investigated the in vitro effects of histone deacetylase inhibitors, trichostatin A and valproic acid, on human leukemic cell lines such as SKNO-1 and Kasumi-1 expressing RUNX1/ETO, Reh expressing TEL/RUNX1 and SKH-1 co-expressing RUNX1/EVI1 and BCR/ABL. We also employed K562 cells expressing BCR/ABL without such a chimera as a control. Treatment with each inhibitor increased acetylated histone 4 in all of these cell lines. Interestingly, proliferation of SKNO-1, Kasumi-1, SKH-1 and Reh cells was significantly suppressed after 3-day culture with trichostatin A or valproic acid, when compared to that of K562 cells. We observed cell cycle arrest and apoptotic induction in the RUNX1 chimera-expressing cells by the propidium iodide staining. Up- and downregulation of cell cycle regulator genes appeared to be the molecular basis for the former, and activation of both extrinsic and intrinsic apoptotic caspases for the latter. We propose histone deacetylase inhibitors to be an attractive choice in the molecular targeting therapy of RUNX1-related leukemia. (Cancer Sci 2008; 99: 414,422) [source]

lnterferon-, gene therapy for cancer: Basic research to clinical application

CANCER SCIENCE, Issue 11 2004
Jun Yoshida
Interferon-, gene therapy for cancer is the first such protocol developed in Japan. Here we describe the development process of our interferon-, gene therapy from basic research to clinical application. Interestingly, the biological and biochemical characteristics of interferon-, gene therapy through transfer of the interferon-(gene into tumor cells by means of cationic liposomes differed from those of conventional interferon-, protein therapy. Interferon-, gene transfer could induce apoptosis in interferon-, protein-resistant tumor cells, such as glioma, melanoma, and renal cell carcinoma. Induction of apoptosis was related to the level of intracellular mRNA of interferon-,, prolongation of the phos-phorylation time of molecules in the interferon-p signal transduc-tion pathway, such as JAK1, Trk2, and STAT1, and activation of DNase ,. In our preclinical study we developed lyophilized cat-ionic liposomes containing interferon-, gene (gene drug) for clinical use and confirmed their safety. Thereafter, we performed a pilot clinical trial in patients with malignant glioma and confirmed the safety and effectiveness of this interferon-, gene therapy. In this review we also comment on the status of gene therapy regulation in Japan. Interferon-, gene therapy is expected to become widely available for clinical use in cancer patients, and this new strategy might be extended to molecular targeting therapy, or used in combination with cell therapy or other therapies. [source]