Research

Colorectal cancer is the fourth-highest cancer in terms of incidence, and second-leading cause of cancer death.  In the US, over 140,000 new cases of colorectal cancer are diagnosed each year, and nearly 50,000 patients die from the disease.  Like most cancers, less-than-optimal efficacy of anti-neoplastic agents is a major barrier to the successful treatment of advanced colorectal cancer.  The high genetic plasticity of neoplastic cells generally leads to rapid emergence of resistance to chemotherapeutic agents, reducing therapeutic effectiveness.  For several years, we have been examining an important class of chemotherapeutic agents that target the pyrimidine biosynthetic enzyme thymidylate synthase (TYMS).  TYMS catalyzes the  reductive methylation of dUMP to form dTMP, making it indispensible for DNA synthesis during cell proliferation and DNA repair. Exposing cells to TYMS-directed antimetabolites, such as fluoropyrimidine analogs (e.g., 5-fluorouracil and 5-fluoro-2'- deoxyuridine), as well as antifolates (e.g., tomudex, AG337, and BW1843), results in the inhibition of TYMS, causing depletion of thymidylate pools, cessation of cell growth, and eventually, cell death. Thus, TS inhibitors have been useful in the treatment of a variety of neoplasms.  However, a large fraction of patients are intrinsically resistant to TYMS inhibitors, and do not respond to these drugs; furthermore, those that do respond typically develop resistance, so that the drugs lose their efficacy.