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Tag Archives: Jewish General Hospital

Friday Science Review: March 18, 2011

Alum Explained

University of Calgary ♦ Published in Nature Medicine, Mar. 13, 2011

During the administration of a vaccine, an antigen is delivered along with another substance, known as an adjuvant, which arouses the immune system and increases overall effectiveness. The most common adjuvant in use today is alum, a trivalent aluminum-containing salt in crystal form.

Many questions related to alum’s mechanisms of action remain unanswered, or were mostly unanswered until the emergence of recent findings from the lab of Dr. Yan Shi at the University of Calgary. Dr. Shi and his lab group discovered that alum interacts with dendritic cells, a specific cell-type in the immune system that specializes in digesting antigenic material and presenting it on the cell surface. There is no specific receptor for alum however, instead it interacts with lipids on the plasma membrane eliciting a lipid sorting mechanism. Sorting of lipids induces a phagocytic response causing an influx of antigen into dendritic cells and an increase in affinity for CD4+ T cells.

Alum has massive implications for human health given the size and importance of the vaccine market. This new insight into dendritic cell response to alum will likely be leveraged to improve upon the efficacy of future vaccines.

Suicide Gene Delivers the Blow

Jewish General Hospital ♦ McGill University ♦ Published in Cancer Gene Therapy, Mar.11, 2011

Combination treatment paradigms for cancer have been under investigation for some time, but the suicide gene approach outlined in this recent research exemplifies the advances that have been made in the area. In this approach a tumour-specific oncolytic virus delivering a fusion construct is paired with a non-toxic prodrug. When the prodrug enters an infected cell containing the suicide transgene it is broken down by the cell’s machinery into toxic metabolites. In essence, the cell commits suicide.

Oncolytic viruses target cancer cells by taking advantage of their genetic abnormalities. A perfect example is vesicular stomatitis virus (VSV), a single stranded RNA virus that grows like wildfire in cancer cells but is unable to populate healthy cells. How? VSV is extraordinarily sensitive to type-1 interferon mediated immune responses. In normal cells that have interferon signaling cascades intact the virus cannot replicate. However, in cancer cells, which have genetic alterations affecting the interferon pathway, the virus survives with relative ease. Researchers utilized a suicide gene (CD::UPRT) in combination with 5-FC, a non-toxic prodrug that is metabolized to the toxic 5-flourocytosine (5-FU) form in the presence of cytosine deaminase. The deamination of 5-FC leads to its conversation to 5-FU, a small molecule drug commonly used in chemotherapeutic regimes for the eradication of cancer. The introduction of 5-FU into the cellular system prevents normal DNA replication, and hence causes cell cycle arrest. In this study researchers showed that the suicide gene strategy was able to trigger oncolysis in a number of VSV-resistant cell strains, including prostate PC3, breast MCF7, B-lymphoma Karpas, and melanoma B16-F10.

The combination scheme investigated here allows for the targeted removal of tumour cells while preserving healthy cells. As such, it circumvents one of the primary barriers associated with the development of efficacious cancer therapeutics − non-selective toxicity. 5-FU is also highly soluble, which causes detriment to neighbouring tumour cells that have been weakly infected, producing a particularly powerful treatment.

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