| Souped-up(效力增强了的) enzymes that
flush poisons out of cells more efficiently than their natural
counterparts(对应的人或物) could alleviate some of the severe side effects of
chemotherapy and so improve the chances of curing cancers. Many anticancer drugs attack tumor cells because they divide more rapidly than heathy cells. But some vital healthy cells also divide faster thanormal, and these are destroyed as well. The most vital cells caught in the chemical cross-fire are those made in the bone marrow(骨髓). Under normal circumstances, these mature into platelets(血小板), which are vital for wound-healing, and white blood cells that fight infections. If levels of these cells fall, patients become dangerously vulnerable to infection and can suffer such severe internal bleeding that treatment has to be stopped. Surviving cancer cells can then re-grow and reduce the effectiveness of the therapy. Bill Fehl and his colleagues at the University of Wisconsin Medical School have engineered an enzyme that could make bone marrow cells resistant to the cancer drugs, so higher doses can be given and side effects reduced. The idea is to take healthy bone marrow cells from patients before they begin chemotherapy, then equip these cells with the genes that make the enzyme drug-resistant. When returned to the patient, the improved bone marrow cells could then withstand heavy doses of the drugs. The natural version of the enzyme—called glutathione Stransferase(谷胱甘肽S转移酶) —is produced mainly in the liver and catalyses(催化) the breakdown of compounds that might otherwise damage DNA in cells. GST also neutralizes(中和) the toxic breakdown products of anticancer drugs, which makes it suitable for protecting bone marrow cells. But natural GST does not work efficiently enough to avoid being swamped by high doses of drugs. GST catalyses a reaction between potentially toxic compounds and glutathione—a peptide (肽) produced in almost all cells of the body. The GST molecule has a cavity, or "active site", where the two molecules are brought close enough to react. This neutralizes the toxin, which passes into the blood to be excreted in the patient's urine. Using machines for synthesizing(结合,使合成)DNA, Fehl and his colleagues made thousands of "scrambled" versions of the parts of the GST gene that make the active site of the enzyme. They inserted these scrambled genes into Escherichia coll. By exposing the bacteria to increasing quantities of the anticancer drug, mechlorethamine(氮芥), Fehl screened out the ones most tolerant to the drug. "By this method, we made enzymes 30 times as efficient as the natural one," says Fehl. In other words, it took 30 times as much drug to kill the bacteria. Fehl has already exposed mice carrying copies of the doctored gene to known carcinogens(致癌物) to see how efficient the gene is at mopping up the toxins. The more efficient it is, the less damage the toxins do and fewer tumors should appear. "We anticipate a significant reduction (in the number of cancers) in the group carrying the gene, "says Fehl, who is still analyzing the results. Fehl's team has applied for a patent covering the technique, and hopes to develop treatments with Systemix, a company based in Palo Alto, California. Brian Ketterer, who heads the Cancer Research Campaign's molecular toxicology group in London, says Fehl's work could be important. But he warns that the proposed strategy would not protect cells lining the gut from chemotherapy drugs. |