Tricking Genes into Killing Cancers

Researchers from the British Cancer Research Campaign have developed a new gene therapy technique that they believe will lead to more effective cancer treatments with fewer side effects.

Writing in the journal Oncogene, Dr. Nicol Keith of the Campaign's Beatson Laboratories at Glasgow University and colleagues reported on their research with the gene telomerase, which is switched on in over 80 percent of human cancers but is usually turned off in normal tissue.

Cancer cells need telomerase to be activated in order for them to continue dividing beyond their normal lifespan.

"With a bit of genetic trickery, we've managed to fool cancer cells to their doom without harming normal cells," said Keith. "I'm optimistic that we could soon have targeted treatments that spare cancer patients the side-effects that many suffer today."

Keith explained that cancer cells often switch on different genes than their healthy counterparts. Some of these genes are only switched on in certain types of the disease, but others are important in a wide variety of cancers. One such gene is telomerase.

The researchers were able to copy the "on-switch" for telomerase and wire it to another gene called nitroreductase, a known anti-cancer gene. Cancer cells that received nitroreductase condemned themselves to death by switching the gene on, thinking they were switching on telomerase. But healthy cells, which already lacked the capacity to turn on telomerase, were similarly not enticed into switching on nitroreductase, thus sparing them from damage.

Nitroreductase does not destroy tumors directly. Instead, it converts a drug called CB1954 - which is normally harmless - into a toxic product that rapidly kills cancer cells. But because healthy cells don't switch on the nitroreductase gene, they cannot activate CB1954 and so are left unharmed. This is the key to the gene therapy's selectivity.

"We're using a sleight of hand to convince cancer cells that they're switching on the telomerase gene - which they need for their survival - when they're actually switching on a gene that will ultimately kill them," Keith said.

SOURCES:
U.K. Cancer Research Campaign (http://www.crc.org.uk)
Oncogene, November 2001; 20(53):7797-7803

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