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Cancer’s next Mmagic bullet may be magic shotgun

Saturday, 16 June 2012

Network approach to drug design may yield more effective and less toxic cancer drugs, UCSF study suggests.

A new approach to drug design, pioneered by a group of researchers at the University of California, San Francisco (UCSF) and Mt. Sinai, New York, promises to help identify future drugs to fight cancer and other diseases that will be more effective and have fewer side effects.

Rather than seeking to find magic bullets — chemicals that specifically attack one gene or protein involved in one particular part of a disease process — the new approach looks to find “magic shotguns” by sifting through the known universe of chemicals to find the few special molecules that broadly disrupt the whole diseases process.

“We’ve always been looking for magic bullets,” said Kevan Shokat, PhD, a Howard Hughes Medical Institute Investigator and chair of the Department of Cellular and Molecular Pharmacology at UCSF. “This is a magic shotgun — it doesn’t inhibit one target but a set of targets — and that gives us a much, much better ability to stop the cancer without causing as many side effects.”

Described in the June 7, 2012 issue of the journal Nature, the magic shotgun approach has already yielded two potential drugs, called AD80 and AD81, which in fruit flies were more effective and less toxic than the drug vandetanib, which was approved by the U.S. Food & Drug Administration last year for the treatment of a certain type of thyroid cancer.

Expanding the Targets to Lower a Drug’s Toxicity

Drug design is basically all about disruption. In any disease, there are numerous molecular interactions and other processes that take place within specific tissues, and in the broadest sense, most drugs are simply chemicals that interfere with the proteins and genes involved in those processes. The better a drug disrupts key parts of a disease process, the more effective it is.

The toxicity of a drug, on the other hand, refers to how it also disrupts other parts of the body’s system. Drugs always fall short of perfection in this sense, and all pharmaceuticals have some level of toxicity due to unwanted interactions the drugs have with other molecules in the body.

Scientists use something called the therapeutic index (the ratio of effective dose to toxic dose) as a way of defining how severe the side effects of a given drug would be. Many of the safest drugs on the market have therapeutic indexes that are 20 or higher — meaning that you would have to take 20 times the prescribed dose to suffer severe side effects.