Health / Israeli development, which improves technology to eliminate certain types of cancer cells, has been successful in initial experiments on animals
Marit Selvin, Haaretz
https://www.hayadan.org.il/proteinsagainstcancer.html
The hybrid proteins attach to receptors on the cancer cells; Once attached, the proteins enter the cells; The proteins work inside the cells and cause their death. Source: School of Medicine, Hebrew University
The approach that guides cancer researchers in recent decades is the development of therapeutics that will uniquely target the malignant cells. To do this, it is necessary to find unique characteristics that are inside the target cells and develop molecules that will block their action. Medicines based on this principle - the best known of which is "Gleevec" - have come into use in recent years and are being successful in the treatment of certain types of cancer.
Another approach is to eliminate the cells using poisons that do not distinguish between a cancerous cell and a normal cell. Medicines based on this approach act like a guided missile: they hit the target by locating identification labels on the outer membrane of the cancer cells, stick to the cells and unload the charge inside them, which causes the cell to die. In order to implement this idea, a molecule must be developed that will consist of two parts: an institute part, which will recognize the identification labels of the cancer cell and target it, and a killing part.
Identification labels are found on the outer membrane of every normal cell: these are receptors that bind antibodies, hormones and growth factors and allow them to penetrate into the cell. Unfortunately, cancer cells do not have unique receptors that characterize only them, which can be used as identification labels. However, many types of cancer are characterized by a huge increase in the number of certain receptors, and these receptors serve as targets for attack. Through genetic engineering, it is possible to produce parts of proteins and fuse them with each other, so that a hybrid protein is created, one part of which recognizes the receptor and binds to it, and the other part consists of a natural substance capable of eliminating the cell.
An anti-cancer drug based on this approach has recently entered medical use. The drug, named Ontak, is a hybrid protein whose targeting part consists of a human-derived growth factor that binds to the receptor, and the killing part consists of the toxin of the diphtheria bacterium; The drug is used to treat a certain type of blood cancer.
But the use of the hybrid proteins encountered a problem. Their killer part, which consists of a plant or bacterial protein that the body does not recognize, provokes a counter-reaction of the immune system. The reaction against the foreign component may weaken its action over time and cause inflammation and damage to internal organs, especially the liver. For these reasons the use of hybrid proteins is limited.
A development by Dr. Chaya Lorberbaum-Galsky from the Department of Cell Biochemistry and Human Genetics at the Hebrew University School of Medicine may overcome the problem. "My assumption was that the hybrid protein should be composed entirely of proteins of human origin, in order to overcome the counter reaction the vaccine The idea was to create a hybrid protein in which the killing part would consist of proteins found naturally in our bodies, involved in the processes of programmed cell death. Such proteins, I hoped, would force the sick cell to commit suicide."
In every cell of the body there is a set of instructions that activates a one-way chain of events that ends in cell death. This suicide system, called apoptosis, is extremely complex. The chain leading to cell death involves proteins that come into action at fixed points: at the beginning, middle and end of the chain. The "executors" of the process are special enzymes, which break down the cell's proteins and its genetic material. Each of them can be used as an effective killing tool.
Lorberbaum-Galsky began testing hybrid proteins in the late 80s. "I read an article in which it was written that ovarian cancer responds to a protein hormone called GnRH, and I thought that this hormone might be suitable for the targeted part of a hybrid protein," she says. "In the laboratory, we engineered a protein with two heads: one consisting of GnRH and the other consisting of a bacterial toxin. When we activated this hybrid protein on cancer cells, we found to our surprise that it was able to enter a wide variety of them, even cells that are not related to the female reproductive system."
The next step was to see if it was possible to force the cancer cell to commit suicide. About three years ago, Lorberbaum-Galsky's team created a hybrid protein, whose targeting part consists of the GnRH protein and whose killing part consists of a human protein that participates in the last step of the chain of events leading to cell death; Its role in the process is to cut DNA.
The new hybrid protein was tested in cultured cancer cells. "We tested cell cultures from different types of cancer, all solid cancers that send metastases. Our hybrid protein, it turned out, caused the death of all those cancers. We also tried hybrid proteins composed of different apoptosis-inducing proteins. All these proteins demonstrated a similar degree of effectiveness in killing the target cells In all cases we observed a similar pattern of 'silent' killing of the malignant cells."
In the next step, the team members tested the hybrid protein in animals. They injected the substance into mice that had colon cancer, which originated in humans. Control mice were injected with only the targeted part of the hybrid protein, and another control group was not injected with the protein at all. The treatment was given for ten days, and the results showed that in more than 90% of the animals that carried the tumor, the tumor completely regressed. The study was published about two months ago in the journal "Clinical Cancer Research."
"The results showed that the human protein we added to the killer part of the molecule effectively entered the nucleus and cut the DNA molecules," Lorberbaum-Galsky says. "This shows us that the cell, thanks to the fact that it knew the protein, directed it to the right place." According to her, "this technology is applicable in a huge variety of diseases, provided we know how to effectively direct the hybrid protein to the cell involved in the disease." Her team is now working on implementing the idea in cases of inflammatory diseases, transplant rejection and allergies. A year ago, Lorberbaum-Galsky founded Target-In in collaboration with the Hebrew University's implementation company.
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