We have learned that we can prevent colon cancer by taking aspirin. However because of the significant side effects such as gastric ulcer, bleeding complications and kidney problems, aspirin is not recommended for the public to prevent colon cancer.
In an effort to prevent colon cancer but avoid the side effects of aspirin, COX-2 inhibitors such as Celebrex® (celecoxib) was developed and tested to see if they could prevent colon cancer without the side effects of aspirin. Unfortunately, we have witnessed that high doses of Celebrex can cause heart attacks which put a significant hold on the development of these drugs as chemopreventative agents.
The studies of Celebrex have been disappointing so far, and we may know why. A recent study let by Dr. Sanford Markowitz (PNAS this week) was able to show that individuals with low levels of 15-PGDH did not benefit from Celebrex therapy. This is an important finding because it may allow selection of patients for chemoprevention (a FIRST) but also to develop novel chemoprevention strategies for individuals who have low 15-PGDH levels. There is now significant efforts to study the molecular mechanisms of 15-PGDH and resistance to Celebrex in mouse models.
How does 15-PDGH levels relate to colon cancer development? Investigators from the Dana Farber Cancer Center (Monica M. Bertagnolli) examined colon biopsies from human patients who had participated in the APC trial of Celecoxib. They found that among these individuals colon 15-PGDH levels varied by 12-fold from lowest to highest. Most importantly, they found that the patients who were resistant to Celecoxib and had developed new colon tumors were all individuals who had low levels of colonic 15-PGDH. Thus in both mice and humans, Celecoxib works to prevent colon tumors only if levels of colonic 15-PGDH are high, while low levels of 15-PGDH leads to Celecoxib resistance.
Both investigators Markowitz and Bertagnolli point out that these findings require additional studies with larger numbers of patients. In the future we need to become much more sophisticated to prevent colon cancer. We are moving away from one size fits all to a tailored strategy in chemoprevention.