A study unveiled in today's issue of Cell highlights a new aspect of cancer cell susceptibility to chemotherapeutic drugs and reinforces the emerging idea that the genetic profile of a tumor may be one of the most important determinants of treatment outcome.

Researchers have known for a few years that one of the body's main defense mechanisms against cancer is the inherent cell death pathway called apoptosis.

This protects us against cancer by causing the death of cells that are growing abnormally, and bypassing this death is one of the critical steps in progression towards cancer.

Many chemotherapeutic agents are thought to work by inducing apoptosis of cancer cells. As part of their ongoing analysis of cancer and the role of apoptosis, Dr. Scott Lowe and colleagues from the Cold Spring Harbor Laboratory in New York have developed a unique mouse model that is a powerful tool for performing cancer cell studies that would be impossible to undertake in human cancer patients.

They have generated mice expressing a specific cancer-causing gene that induces malignant tumors resembling human non-Hodgkin's lymphoma.

In their current study, the research team used these mice to look at the response of tumors with different genetic mutations to the chemotherapeutic agent cyclophosphamide (CTX), a drug that is used to treat human cancers.

Although the tumors they analyzed were all initiated by the same genetic signal, there were marked differences in treatment responses depending on the rest of the genetic makeup of the tumor cells.

As expected, the researchers found that successful action of CTX depended on its ability to cause apoptosis; cells that were more resistant to apoptosis were also more resistant to the drug.

However, they also uncovered evidence that a separate cell death pathway called senescence plays a very important role in the overall response to the drug.

Cancers with mutations that make them resistant to both apoptosis and senescence were markedly more resistant to the drug treatment, and, even with the drug present, progressed rapidly to a point at which they were lethal.

The drug was essentially ineffective at fighting these tumors. The researchers also found that drug-induced senescence effects were most pronounced when apoptosis was blocked, and suggest that senescence may function as a “backup” to apoptosis.

These results highlight the new idea that cell senescence is an important contributor to cancer, and particularly to the response to chemotherapeutic drugs.

For some tumors, senescence pathways may be even more important than apoptosis in cancer growth and treatment outcome. The new findings also serve to strengthen the growing view that a given tumor's genetic makeup can have a profound effect on its response to chemotherapy.

Combining our knowledge of the activity of drugs with information about the genetic makeup of a tumor "will eventually allow us to use conventional agents more effectively by applying them to tumors in which they are most likely to be effective,” explains Dr. Lowe.


[Contact: Dr. Scott Lowe]

03-May-2002