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Numbers Game

In her search to understand why some patients seem to he resistant to some otherwise—effective cancer drugs, Wendy Gati not only spends a good deal of time in her pharmacology lab, but she can regularly be found on the road to and from the airport.

That's because, instead of looking for answers using cells cultured in the laboratory, the University of Alberta pharmacology professor is working with cells from patients. "Cells isolated from patients are different from cells grown in culture," says Gati, who not only works with Edmonton-area clinicians but has two dozen clinical collaborators from across Canada who send her blood samples via air cargo express. "We have a system worked out to receive and do assays within 24 hours," she says.

Gati is particularly interested in a class of drugs that are known as nucleoside analogs because they mimic naturallyoccuring breakdown products originating from the nucleic acid contained in DNA. Nucleoside analogs are some of the most effective drugs for the treatment of the leukemias — a group of malignant disorders of the white cells of the blood. But they aren't perfect. "They work," says Gati, "but they don't work for everybody, and sometimes they lose their effectiveness — in some leukemias a large percentage of patients relapse because of resistance."

Working with blood cells from patients and using a unique fluorescent probe, Gati is looking at one possible resistance mechanism. "In order to be effective, the drug must penetrate the cellular membrane and enter the cell," explains Gati. To do so it has to he carried across the cell membrane by proteins, called nucleoside transporters, that mistake the analog drugs for the natural nucleosides they mimic.

"We have good evidence that the cells of different patients have different numbers of transporters," she says, "We think that patients with few transporters may respond poorly to treatment." She has also found that there is often a variance in the number of transporters in different cells in the same patient — which opens up the possibility of drug resistance developing. "The cells with few transporters survive and grow, and would repopulate the tumor, and the leukemia would come back," says Gati. "One resistant cell is all it takes."

Key to Gati's work is the special fluorescent probe that makes it possible for her to enumerate transporters in a cell within two or three hours after receiving a sample. She believes that such a probe could he routinely used to screen patients and individually tailor treatment protocols, and she hopes to soon have sufficient data to provide the ammunition to make that happen.

"We have to have statistically significant results to convince clinicians that lack of transporters is an important part of the development of drug resistance," said Gati. "It's a numbers game."

Published Winter 1999.

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