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Opening Doors

To give a sence of her research, Carol Cass paints a word picture of a single human cell as a house. "Think of it as having many different rooms — a furnace room, a garbage room, a room for producing new parts; the nucleus could he the library, where you could find all the information needed to reproduce the house."

Cass who is chair of the University of Alberta's Department of Oncology, is interested in the doorways to those many rooms and to the house itself — or more precisely, perhaps, in the doormen whose job it is to either usher guests into the room or refuse entry to unfamiliar faces.

"We're really interested in understanding the role of transporters," she says, "not only because they are innately interesting, but because we need to understand what's happening if we want to interfere with it." Working with clinician John Mackey, a faculty member in oncology, Cass is investigating a major problem relating to chemotherapy treatment — the development of drug resistance.

"We've seen in the test tube cancer cells lose their doors and become insensitive to nucleoside drugs," says Cass. (Nucleoside drugs are compounds whose shape is tailored to be so similar to that of nucleosides—which are natural precursors of nucleic acid — that the "doormen" of malignant cells let them inside.) She and Mackey want to know why the transporters that previously carried the drug across the cell membrane no longer do so. To address this question, Cass and Mackey are collecting "bits of cancer" from actual patients and studying the transporters themselves, as well as the genetic makeup of the cancer cells, using the lastest scientific techniques.

"One of the goals," explains Mackey, "is to determine which patients will benefit from treatment. Ideally, if we had a hundred patients, instead of treating all 100, we would pick out the likely winners and only treat them. That would not only spare the others the side effects, but we wouldn't waste time which could be spent looking at other treatment strategies." In the clinic, says Mackey, it can take as long as three months to know if a patient is responding positively to chemotherapy treatment. A reliable predictive test could save some of that precious time.

The University of Alberta has long been a leader in transporter research. Much of the work being done in Cass's lab relates to the nucleoside transporter known by the nickname "es." Discovered in 1969 at the University of Alberta by Alan Paterson, now a professor emeritus of pharmacology, this protein was the first nucleoside transporter discovered and has since been shown to be the most common, opening doors both to the cell and to its various "rooms." A handful of other transporters have been discovered since, and the chemical structure of four of the transporters has been defined.

"We want to understand them at the level of protein — how they're folded and what they look like — and there are still many questions to answer at the level of the cell," says Cass. "How do the transporters know where to go? Why do they sometimes stop working? And how can we influence the process to help our patients?"

Published Winter 1999.

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