Methods for improving the safety of fluoropyrimidine anticancer drugs

Jacobs’ thesis is about a commonly used class of anti-cancer drugs called fluoropyrimidines. Approximately one in four patients who receive chemotherapy with these drugs experience serious and sometimes even lethal side effects. The goal of Jacobs work was to improve the safety of these anti-cancer drugs. In particular, his work focused on an oral form of fluoropyrimidine, the drug capecitabine. The first part of the thesis revolves about a number of clinical tests that can be used to predict whether a patient might develop the severe side effects. Patients who get really ill from fluoropyrimidines often have a defect in an enzyme called dihydropyrimidine dehydrogenase (DPD), which is essential for breaking down the drug in the body. Jacobs discusses the development of two tests that can be used to determine the activity of DPD. Both of these test proved to be reliable an accurate. He also discusses a method to determine the activity of another enzyme, thymidine phosphorylase (TP). A high TP activity can lead to rapid breakdown of the drug and rapid release of a high level of cytotoxic metabolites. The second part of Jacobs’ thesis describes a number of translational and clinical studies that were designed to determine variation in the activity of relevant enzymes. One of the findings was that the activity of DPD varies throughout the day. The enzyme turns out to be most active early at night. The DPD activity also turns out to drop significantly after patients with colorectal cancer have received surgery for liver metastases. However, this drop in activity is temporary. Jacobs therefore recommends that adjustment of the fluoropyrimidine dose should not be based on measurements of DPD activity that were made in the days following the surgery. The third part of the thesis discusses a number of aspects of the pharmacokinetics of capecitabine. Among other things, Jacobs shows that the oral tablets release the drug quite rapidly and that this release can be slowed down by adjusting the tablet formulation by the addition of excipients in the outer layer of tablet. In the fourth and last part of his thesis Jacobs shows that a dosing schedule of capecitabine, which is adapted to diurnal changes in DPD activity, is a promising way to improve both the efficacy and safety of capecitabine