Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions.

Spontaneous tumors regression has been associated with microbial infection for 100s of years and inspired the use of bacteria for anticancer therapy. Dr. William B. Coley (1862-1936), a bone- sarcoma surgeon, was a pioneer in treating his patients with both live bacterial-based and mixture of heat-killed bacteria known as "Coley's toxins." Unfortunately, Coley was forced to stop his work which interrupted this field for about half a century. Currently, several species of bacteria are being developed against cancer. The bacterial species, their genetic background and their infectious behavior within the tumor microenvironment are thought to be relevant factors in determining their anti-tumor effectiveness in vivo. In this perspective article we will update the most promising results achieved using bacterial therapy (alone or combined with other strategies) in clinically-relevant animal models of cancer and critically discuss the impact of the bacterial variants, route of administration and mechanisms of bacteria-cancer-cell interaction. We will also discuss strategies to apply this information using modern mouse models, molecular biology, genetics and imaging for future bacterial therapy of cancer patients.

Neoadjuvant administration of Semliki Forest virus expressing interleukin-12 combined with attenuated Salmonella eradicates breast cancer metastasis and achieves long-term survival in immunocompetent mice.

BACKGROUND: Metastatic breast cancer is a major cause of death among women worldwide; therefore efficient therapeutic strategies are extremely needed. In this work we have developed a gene therapy- and bacteria-based combined neoadjuvant approach and evaluated its antitumor effect in a clinically relevant animal model of metastatic breast cancer. METHODS: 2×10(8) particles of a Semliki Forest virus vector expressing interleukin-12 (SFV-IL-12) and/or 2×10(7) units of an aroC (-) Samonella Typhimurium strain (LVR01) were injected into 4T1 tumor nodules orthotopically implanted in mice. Tumors were surgically resected and long-term survival was determined. IL-12 and interferon-γ were quantified by Enzyme-Linked ImmunoSorbent Assay, bacteria was visualized by inmunohistochemistry and the number of lung metastasis was calculated with a clonogenic assay. RESULTS: SFV-IL-12 and LVR01 timely inoculated and followed by surgical resection of tumors succeeded in complete inhibition of lethal lung metastasis and long-term survival in 90% of treated mice. The combined therapy was markedly synergistic compared to each treatment alone, since SFV-IL-12 monotherapy showed a potent antiangiogenic effect, being able to inhibit tumor growth and extend survival, but could not prevent establishment of distant metastasis and death of tumor-excised animals. On the other hand, LVR01 alone also showed a significant, although limited, antitumor potential, despite its ability to invade breast cancer cells and induce granulocyte recruitment. The efficacy of the combined therapy depended on the order in which both factors were administered; inasmuch the therapeutic effect was only observed when SFV-IL-12 was administered previous to LVR01, whereas administration of LVR01 before SFV-IL-12 had negligible antitumor activity. Moreover, pre-treatment with LVR01 seemed to suppress SFV-IL-12 antiangiogenic effects associated to lower IL-12 expression in this group. Re-challenged mice were unable to reject a second 4T1 tumor; however 100% of them could be totally cured by applying the same neoadjuvant combined regimen. To our knowledge, these are the most encouraging results obtained to date in a post-operatory setting using the highly aggressive 4T1 animal model. CONCLUSIONS: SFV-IL-12-based gene therapy combined with Salmonella LVR01 neoadjuvant administration has a synergic antitumor effect and may be a promising therapeutic option to prevent and/or eradicate pre-operatory metastasis in locally advanced breast cancer.

Antioxidant activity of uruguayan propolis. In vitro and cellular assays.

The antioxidant capacity of propolis from the southern region of Uruguay was evaluated using in vitro as well as cellular assays. Free radical scavenging capacity was assessed by ORAC, obtaining values significantly higher than those of other natural products (8000 µmol Trolox equiv/g propolis). ORAC values correlated well with total polyphenol content (determined by Folin-Ciocalteu method) and UV absorption. Total polyphenol content (150 mg gallic acid equiv/g propolis) and flavonoids (45 mg quercetin equiv/g propolis) were similar to values reported for southern Brazilian (group 3) and Argentinean propolis. Flavonoid composition determined by RP-HPLC indicates a strong poplar-tree origin. Samples high in polyphenols efficiently inhibit low-density lipoprotein lipoperoxidation and tyrosine nitration. In addition, Uruguayan propolis was found to induce the expression of endothelial nitric oxide synthase and inhibit endothelial NADPH oxidase, suggesting a potential cardiovascular benefit by increasing nitric oxide bioavailability in the endothelium.

Investigación de metapneumovirus humano en pacientes hospitalizados: estudio multicéntrico / Research of human metapneumovirus in hospitalized patients: a multicenter study

Introducción: las infecciones respiratorias agudas bajas (IRAB) son la primer causa de hospitalización a lo largo del año. La etiología viral es la más frecuente. El Metapneumovirus humano (MNVh) ha sido vinculado a las IRAB con aspirado negativo para Virus respiratorio sincicial (VRS) y Adenovirus (AD). Objetivo: determinar la prevalencia, epidemiología, clínica y severidad de las infecciones por MNVh, e intentar detectar un patrón radiológico relacionado con el mismo. Métodos: se estudiaron niños entre 0 y 2 años de edad internados por IRAB en el Centro Hospitalario Pereira Rossell, Hospital Central de las Fuerzas Armadas, Hospital Policial, Hospital Británico y Asociación Española Primera de Socorros Mutuos en el período 1 de abril al 30 de noviembre de 2006. Los aspirados nasofaríngeos fueron analizados en la Sección Virología de la Facultad de Ciencias. Resultados: se estudiaron 185 pacientes, obteniéndose 17 resultados positivos para MNVh (9,2%), con 9 coinfecciones con VRS. La mayoría de los pacientes tenían 6 meses o menos de edad. Las manifestaciones clínicas principales fueron polipnea, tirajes y sibilancias. Los principales hallazgos radiológicos fueron infiltrado intersticial difuso e hiperinsuflación. Ningún paciente requirió internación en unidad de cuidados intensivos y no hubo casos fatales. Conclusiones: la prevalencia, características clínicas y evolutivas de las infecciones por MNVh no mostraron diferencias frente a las producidas por el VRS.