The basics of chemotherapy

Dr. Ned Sharpless is associate director for translational research at the UNC Lineberger Comprehensive Cancer Center. He explains the basics of chemotherapy and how the Chapel Hill-based company he founded is trying to make this toxic treatment more tolerable. Questions and answers have been edited.

Q: How does traditional chemotherapy work?

For the first 50 years of oncology, the most effective cancer drugs have been cytotoxic agents, or what we call traditional chemotherapy. These traditional drugs keep cells from making new DNA, which cancer cells must have to grow and divide. The problem is that there are a lot of dividing cells that you need that are not cancer, and that is why the drugs are toxic. So it would be nice to have a way to only kill cancer replication, which is what newer "targeted" therapies are trying to do.

Q: You talk about the effect of chemotherapy on cells that are replicating, but then it can also affect nonreplicating cells, such as those in the brain. What exactly is "chemobrain"?

Ten years ago, we told patients undergoing chemo that they would lose their hair, throw up, be in danger of getting an infection, but we didn't appreciate that they also would have trouble thinking. Cognitive decline is a very real and underappreciated symptom of treatment. Almost all of my patients say their brain feels funny; they can't concentrate; they can't read books. Most of them get better, but not all of them do. It is a very difficult problem to study, because we don't know what - the chemo, the steroids, the psychological trauma - is at fault.

Q: What kind of research is being done to identify ways to target cancer cells and spare other dividing cells, such as those in the bone marrow and the gut?

The hope is to find cellular signaling pathways to which cancer cells are addicted and block them so only normal cells will survive. That has, in some cases, come to fruition, but I don't think we have yet seen the blockbuster drug that the targeted revolution has promised. The issue is that while normal cells are well-behaved in how they divide, cancer cells will find a way to divide that isn't blocked by your drug.

That is the thing about the DNA-damaging agents that is worth repeating. Although they are nasty and have terrible side effects, they are capable of curing your cancer and making it never come back. So we will require those drugs for many years to come.

Q: If these old treatments are here to stay, what can be done to make chemotherapy more bearable?

There is a lot of work on therapies to protect the bone marrow from DNA damage. That is what our company, G-Zero, has been working on. We are developing ways to induce something called pharmacologicalquiescence, which arrests bone marrow cells, but not cancer cells, in a state where they can repair their DNA. You have to be careful, though, because treatments that help the patient survive better may make the tumor survive better, too. Nobody wants that.