办事指南

Precision killing

点击量:   时间:2019-03-08 08:04:00

By Philip Cohen NEW cancer treatments could destroy tumours without the serious side effects caused by current methods. Scientists have shown they can exploit a genetic flaw in tumour cells, which they hope will allow them to be killed without harming healthy cells. Because cancer cells arise from cells in a patient’s own body, nearly all their key functions are performed by the same genes and proteins as in healthy cells. So treatments that interfere with any of the hundreds of genes that carry out basic life functions, such as replicating the chromosomes, have been off limits, since these would also endanger normal cells. For that reason, the search for cancer treatments has focused on the tiny number of clear-cut genetic and physiological differences in these renegade cells. “A lot of cancer research has been a hunt for these elusive, tumour-specific targets,” says Vince Stanton, a molecular biologist at the biotech company Variagenics in Cambridge, Massachusetts. Working with Stanton’s team, David Housman of the Massachusetts Institute of Technology has exploited a subtle but vital difference between tumour cells and healthy ones. The difference stems from the fact that genes are inherited in pairs, one copy from the mother’s chromosome and one from the father’s. These copies often differ slightly in their DNA sequence. Cancer cells often lose sections of one or other chromosome during their uncontrolled growth. So they rely on a single version of many genes to survive. Housman reasoned that a drug that attacks the specific form of the gene remaining in the cancer cell would kill it, while healthy cells would have a second version of the gene, allowing them to survive. Stanton and his team have now tested the idea with a target gene called RPA70, which produces a protein required for copying chromosomes. They flooded cancer cells with tiny snippets of chemically modified DNA called oligonucleotides that effectively inactivate the cells’ version of the RPA70 gene. They did this by binding to the RNA copies of the gene used to make the protein. Only about 10 per cent of the cells survived an attack from the DNA snippets. But when the killer DNA sequence was changed to match a different form of RPA70, about 40 per cent of the cells survived, suggesting that it would do relatively little damage to healthy cells (Molecular Pharmacology, vol 56, p 359). Stanton says this discriminating power already puts the oligonucleotides on a par with some existing anticancer drugs. But he believes the oligos could be redesigned, using state-of-the-art chemistry, to get a discriminating power of up to 100. “This lays the foundation for a very clever anti-tumour strategy,” says Bert Vogelstein, a cancer geneticist at Johns Hopkins University in Baltimore. He says the key to the success of the technique will be whether large enough doses of oligonucleotides can be delivered to tumours in patients. Stanton’s team is already thinking along those lines,