Thursday 11 August 2005
CANCER RESEARCH UK funded scientists have developed a series of powerful stealth anti-cancer drugs that can sneak into tumours and destroy them, without causing damage to surrounding healthy cells, a study published in the Journal of Medicinal Chemistry reveals today*.
The research, carried out by scientists at The Institute of Cancer Research, showed that the drugs substantially delayed tumour growth in experiments on human breast cancer cells and in rodent animal models. This research could lead to improved treatment and survival for cancer patients in the future.
The therapy involves sending a ‘scout’ enzyme to a tumour so marking it for destruction. The enzyme is designed to attach and infiltrate only cancerous cells. Here the enzyme lays dormant until non-toxic drugs, called prodrugs, are given. These prodrugs only become active when they react with the ‘scout’ enzyme in the cancerous cell. The enzyme acts as a switch to turn the harmless prodrug molecules, into a potent cancer killing drug.
The research team, led by Professor Caroline Springer, looked at how these drug compounds work in the method of drug delivery called gene-directed enzyme prodrug therapy (GDEPT).
Standard cancer treatments, such as chemotherapy, treat cancer anywhere in the body by indiscriminately attacking all cells in the region. The treatment damages healthy cells as well as cancerous ones, which is why patients have side effects. These can include nausea, fatigue and hair loss. In GDEPT, normal cells should not be affected by the treatment, and this could mean fewer side effects for patients in the future.
Previous prodrugs of this type have often not been powerful enough to reach the enzyme that has been sent to the affected cell. What is unique about this study is that the scientists have been able to get the prodrugs to cross through the cell’s membrane into the cell itself more efficiently.
The researchers tested the eight prodrugs on three variants of human breast cancer. Six of the compounds were found to be effective in targeting the affected cell lines, with three being particularly effective in delaying tumour cell growth.
The six positive compounds were then tested in animal models. Two compounds resulted in a substantial delay to tumour development, and another two cured two models of their tumours.
Professor Caroline Springer, of the Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, says: "We think these drugs are a very promising way forward for cancer treatment. They allow you to deliver a drug at a high concentration, which you wouldn’t normally be able to do, as it is too toxic for the rest of the body. Although this treatment is more complex than many types of therapies, the fact that it can be so selective in treating cancer means that it is worth exploring further.
“At least one of the eight drugs we developed has been identified as a good candidate for testing GDEPT in clinical trials."
Professor Springer adds: "The key importance of this work lies in expressing the ‘scout’ enzyme, which enables the drugs to be selective as to which cells they target."
Professor John Toy, Medical Director at Cancer Research UK, says: “Prodrugs potentially offer a localised treatment for cancer that allows drugs to be targeted specifically to tumours. This type of therapy should theoretically work and is showing promise. Identifying further drugs as targets for GDEPT is an important step if this treatment is to become a viable reality for patients in the future.
"The benefits that this therapy could offer, in terms of more comfortable treatment and reduced side effects, could greatly improve the quality of life for people living with cancer or allow larger doses to be prescribed. The real test will come when the prodrugs go to clinical trials and we are able to analyse closely how well the treatment works in patients."
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Notes to editors
*Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy. Lawrence C. Davies, Frank Friedlos, Douglas Hedley, Jan Martin, Lesley M. Ogilvie, Ian J Scanlon, and Caroline J. Springer. Journal of Medicinal Chemistry. August 11 2005. Volume 48, Issue 16, Pages 5321-5328.
The enzyme used in this study was carboxypeptidase G2 (CPG2, glutamate carboxypeptidase) derived from Pseudomonas RS16.
In GDEPT, the enzyme is targeted onto the tumour by a virus, or via a direct injection.
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