Technique coupled bioengineered proteins with a drug that prevents protein breakdown, explains Nature Medicine paper.

Investigators at the Stanford University School of Medicine have found a way to fine-tune the activity of individual proteins in cells and living mammals. The researchers say that it provides a new tool for the development of anticancer proteins.

The new technique can control the speed with which the protein is broken down through a reversible process. The rate of a protein’s degradation can be increased or decreased by supplying more or less of Shield-1, a drug that prevents proteins from being degraded. This allows scientists to study the biological effects of slightly increasing or diminishing a protein’s activity inside a cell over short a time frame.

The procedure, tested in mice, involves pairing specially bioengineered proteins with Shield-1. The degradation-vulnerable bioengineered proteins were each produced by attaching the gene coding for a protein to another DNA sequence coding for the small extra piece that flags the protein for rapid degradation. The scientists then inserted the altered gene into a virus capable of infecting cells and introducing the altered gene into the cells’ genomes.

The team grafted cultured tumor cells under the skin of immunologically impaired mice. In the absence of Shield-1, the mice developed numerous tumors. When the tumor cells were first pretreated with Shield-1, they secreted IL-2 preventing any initial tumor growth. If Shield-1 was withheld at first and then administered to the mice five days after the grafts, tumors that had developed in those first few days regressed. By day 14, the tumors were gone.

Another set of experiments employed a mutant virus that had been previously developed as a cancer therapy. Researchers inserted the gene for a bioengineered, degradation-prone form of a cell-killing protein into the specialized virus. They then administered it intravenously to tumor-bearing mice.

When no Shield-1 was provided, the tumor growth was only slightly diminished. But if Shield-1 was supplied three days after infection, when the virus had established a solid foothold in the tumors but been cleared from normal cells, tumors were completely eradicated in 90% of the mice. Meanwhile, normal cells were spared the substance’s lethal effects.

The paper was published online yesterday in Nature Medicine.

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