Promising Therapeutic Strategy (promising + therapeutic_strategy)

Distribution by Scientific Domains

Selected Abstracts

Tissue biomarkers in renal cell carcinoma: Issues and solutions,

CANCER, Issue S10 2009
Arianna Di Napoli MD
Abstract Renal cell carcinoma (RCC) is an aggressive malignancy that is associated with a high rate of metastasis. Although several promising therapeutic strategies are now available for the treatment of patients with metastatic kidney cancer, the prognosis of these patients remains poor. Research is ongoing to identify RCC-specific biomarkers that can improve early diagnosis, surveillance of tumor progression, and prediction of patient prognosis. The identification of biomarkers that may predict response to specific therapies also will be useful in stratifying patients with RCC for treatment selection. Unfortunately, biomarker detection and measurement in kidney tumor tissues can be biased significantly by the lack of standardization in tissue sample acquisition, storage, and analysis. Consequently, the establishment of standardized operating procedures is necessary to maximize the accuracy of tissue-based biomarker assays. Herein, the authors discuss current issues in tissue-based translational research aimed at identifying clinically useful biomarkers for kidney cancer. Cancer 2009;115(10 suppl):2290-7. 2009 American Cancer Society. [source]

Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to Bedside

Bert W. O'Malley Jr MD
Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source]

Bis(1H -indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro

Florian Heidel
Summary Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H -indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of both compounds with chemotherapy revealed synergistic effects in apoptosis assays. The compounds did not show significant toxicity in human bone marrow cells derived from healthy donors. Compound102 overcame resistance to PKC412 within a non-myelotoxic dose-range. Western Blotting experiments of 32D-FLT3-ITD cells showed dose-dependent dephosphorylation of FLT3-ITD and of its downstream targets STAT5, AKT and ERK upon incubation with either compound. In conclusion, bis(1H -indol-2-yl)methanones overcome resistance mediated by FLT3-ITD mutations at position N676 and show strong efficacy in FLT3-ITD-positive cells alone as well as in combination with chemotherapy. We propose that further development of methanone compounds overcoming resistance to currently established FLT3-TKIs is an important step forward to an anticipated need within our future therapeutic algorithm in FLT3-ITD-positive AML. [source]

The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy

Alessandra Gaeta
The variety of factors and events involved in neurodegeneration renders the subject a major challenge. Neurodegenerative disorders include a number of different pathological conditions, which share similar critical metabolic processes, such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. In this review, Alzheimer's disease, Parkinson's disease and prion disease are discussed, with the aim of identifying common trends underlying these devastating neurological conditions. Chelation therapy could be a valuable therapeutic approach, since metals are considered to be a pharmacological target for the rationale design of new therapeutic agents directed towards the treatment of neurodegeneration. British Journal of Pharmacology (2005) 146, 1041,1059. doi:10.1038/sj.bjp.0706416 [source]

Local interferon-, gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster

CANCER SCIENCE, Issue 3 2007
Hidehiko Hara
The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN-, did not show cross-species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN-, effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN-, augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN-, gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN-, adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM-1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and natural killer cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM-1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN-, gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity. (Cancer Sci 2007; 98: 455,463)) [source]

Mast cell-mediated airway remodelling

Y. Okayama
Summary Airway structural changes (remodelling) in asthma include increased smooth muscle mass, mucus gland hypertrophy, deposition of extracellular matrix components, thickening of reticular basement membrane, and angiogenesis. The extent of remodelling correlates with severity of asthma, and since patients with extensive remodelling may be resistant to steroids therapy, prevention of airway remodelling is a promising therapeutic strategy for curing patients with severe asthma. Mast cells play a pivotal role in allergic inflammatory diseases including asthma and rhinitis. Both early-phase mediators such as tryptase and chymase and late-phase mediators such as cytokines released by mast cells are capable of modulating airway smooth muscle cell function and inducing goblet cell hyperplasia. Nasal remodelling in patients with rhinitis seems far less extensive than that which occurs in bronchi of asthmatic patients. Because cytokine production by smooth muscle cells may partly explain the differences in remodelling at these two sites, further investigation of the interaction between human mast cells and airway smooth muscle cells is required to identify new therapeutic strategies for reducing airway remodelling in asthma. [source]