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Thomas L Sims, Mackenzie McGee,
Regan F Williams,
Adrianne L Myers,
Lorraine Tracey,
J Blair Hamner,
Catherine Ng,
Jianrong Wu,
M Waleed Gaber,
Beth McCarville,
Amit C Nathwani,
Andrew M Davidoff
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ABSTRACT: Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS.
Molecular Cancer Therapeutics 03/2010; 9(3):761-71. · 5.23 Impact Factor
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ABSTRACT: Trichostatin A (TSA) is a potent histone deacetylase inhibitor and has demonstrated significant antitumor activity against a variety of cancer cell lines. Type I interferons have also shown significant antitumor as well as antiangiogenic activity. In this study, we examined the effectiveness of combination therapy of TSA and interferon beta (IFN-beta) on human neuroblastoma cells in vitro and in vivo using a murine model of retroperitoneal neuroblastoma.
For in vitro experiments, plated human neuroblastoma cells (NB-1643 and NB-1691) were treated with vehicle or with IFN-beta, TSA, or both for 24 hours. Cytotoxicity was assessed by counting cells and expressing the results as a percentage of controls. Expression of the tumor suppressor p21(Waf1) was assessed by Western blot. For in vivo experiments, retroperitoneal neuroblastomas were established in severe combined immune deficiency (SCID) mice. Interferon beta was given using a gene therapy approach, administering 1.5 x 10(10) particles of an adeno-associated virus vector encoding human IFN-beta (AAV hIFN-beta) via tail vein as a single dose per mouse. Trichostatin A was given at a dose of 5 mg/kg every 48 hours subcutaneously. Treatment groups included controls, AAV hIFN-beta alone, TSA alone, and AAV hIFN-beta together with TSA. Tumor volume was assessed 2 weeks after the treatment began.
After 24 hours, treatment with IFN-beta, TSA, and a combination of both resulted in a 45.3%, 68.1%, and 75% reduction in cell count relative to controls in the NB-1691 cell line. In the NB-1643 line, cell counts were reduced by 23%, 58%, and 62.3% respectively. In addition, NB-1691 cells treated with TSA showed increased expression of p21(Waf1) on Western blot. For in vivo experiments, control-, AAV hIFN-beta-, TSA-, and combination-treated tumors had the following final volumes: 1577.7 +/- 264.2 mm(3) (n = 3); 128.5 +/- 74.4 mm(3) (n = 4; P = .0001); 1248.7 +/- 673.9 mm(3) (n = 4; P = .48); and 127.5 +/- 36.8 mm(3) (n = 4; P = .0007), respectively.
Neuroblastoma, because of its unique biology, continues to be a challenging tumor to treat, and many times these tumors are refractory to standard chemotherapeutic regimens. These data show that both TSA and IFN-beta inhibit neuroblastoma growth and that the combination may potentially provide a unique way to treat this difficult disease.
Journal of Pediatric Surgery 02/2008; 43(1):177-82; discussion 182-3. · 1.45 Impact Factor
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ABSTRACT: The variability of the course of infection by Streptococcus pneumoniae is well known but poorly understood. Most animal models of pneumonia, sepsis or meningitis have been forced to use site-specific bacterial inoculation to mimic localized human infection. This study examined the differences in the progression of disease-causing strains D39 (serotype 2), A66.1 (serotype 3) and TIGR4 (serotype 4) using isolates transformed with the Gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r). Expression of the lux operon results in bioluminescence, permitting the detection of the bacteria within a living animal while using a CCD camera. Mice infected intranasally with A66.1 developed only pneumonia, those challenged with D39 experienced high-grade sepsis, while TIGR4 infection resulted in low-grade pneumonia and bacteremia ultimately progressing to meningitis. Quantitative analysis of bacterial titers confirmed these patterns, which were consistent across different lineages of mice. Mice anesthetized with ketamine and xylazine developed more severe forms of the disease compared with isoflurane. These studies unambiguously characterize 3 distinct models of the natural course of pneumococcal infection. Mapping these models provides a framework for detailed molecular modeling of pneumococcal virulence determinants at specific stages of disease.
Scandinavian Journal of Infectious Diseases 02/2003; 35(9):647-52. · 1.72 Impact Factor
