NEWS

Can We Predict Response to 5-FU?

Jean McCann

It may now be possible to predict which patients with colorectal cancer will respond to treatment with 5-fluorouracil alone or in combination for colorectal cancer, it may be possible to predict if patients will respond to treatment.

Patrick Johnston, M.D., of the University of Belfast, claims that by using just two molecular markers—high thymidylate synthase (TS) levels, and mutant p53—"you can basically predict 100% of patients that will not respond to fluoropyrmidines." TS is the final step in the pathway to synthesis of thymidine, which is needed to produce DNA, thus making it an alluring drug target.

Speaking at the second annual European Conference on Perspectives in Colorectal Cancer, Johnston pointed out that the available treatments for colorectal cancer are suboptimal, and despite 4 decades of very active investigation, fluorouracil remains the most active agent available. However, he noted that new drugs and drug combinations are continually coming on the scene.

"In the 1980s and early 1990s it was 5-FU with leucovorin modulation, but now we have several classes of new compounds that may have significant activity," he said. "Nonetheless, despite new drug development, we have also begun to develop new approaches in the way we think about it."

Toward that end, both in vitro and later clinical studies have found TS levels predictive of response to chemotherapy, and that the more advanced the stage of disease, the higher the TS levels were likely to be. Some clinical studies have also shown TS levels to be predictive of both disease-free survival and overall survival, he said.

He noted that Peter Danenberg, Ph.D., of the University of Southern California at Los Angeles, and his colleagues have done extensive work on TS levels in a variety of metastatic colorectal, gastric, and esophageal cancers. Those studies have "basically all concluded that if you have a low TS level and you are treated with a fluoropyrmidine, you’re likely to respond," Johnston said. 5-FU is a prodrug that, after its conversion to 5-fluoro-2-deoxyuridine monophosphate (FdUMP), inhibits the important enzyme involved in the synthesis of thymidylate.

Johnston said his group recently worked with the Danenberg group at USC to modify a reverse-transcriptase PCR technique to look at a variety of markers, including TS and p53, using paraffin-embedded tissue to do these studies. These types of studies had previously been impossible, he added.

But what relationship, if any, is there between thymidylate synthase expression and p53?

"There is laboratory information suggesting an interaction at the molecular level," so that almost all patients with a high TS level and mutant p53 can be predicted not to respond to fluoropyrimidine therapy, he said. "So there’s something going on between TS and p53 regarding cell death and the apoptotic pathways involved, and hopefully that’s something we can begin to unravel over the next several years."

Another molecular marker that has drawn more attention recently is microsatellite instability. Some of the chromosomes relating to microsatellite instability contain some of the very important genes known to be involved in colorectal cancer such as p53, and the APC (a marker in hereditary colon cancer) and DCC (deleted in colorectal cancer) genes.

The molecular phenotype of colorectal cancer has thus begun to reveal important clues about the disease. "For sure," he said, "TS and p53 levels definitely predict response to fluorpyrimidine therapy in the metastatic disease setting, and future studies must further address the importance of the biology of this disease."

Some of the newer fluoropyrmidines like capecitabine (Xeloda), and oral uracil/ftorafur plus leucovorin (Orzel) are fluoropyrimidines that are given orally, and with fewer side effects than are seen with the standard regimens which have to be given by vein, although the newer fluorpyrimidines have not so far shown a survival benefit in clinical trials, according to Chris Twelves of the Cancer Research Campaign in Glasgow, U.K.

While TS and p53 are important markers for response to 5-FU, it may be that in the future, combination therapy of 5-FU with newer drugs like oxaliplatin and irinotecan, which hit even more molecular targets, might be the way to go, especially for advanced disease.

And, as Professsor Jim Cassidy of the University of Aberdeen put it during a session, "I personally believe that, in the future, oral fluoropyrimidines will entirely replace infusional 5-FU regimens." They have fewer side effects, and, obviously, patients prefer oral therapy."

In the meantime, though, predicting response to the long-time gold standard for the treatment of colorectal cancer, 5-FU, is an important goal, and there now appears to be a novel way to do it.



             
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