The Use of Thymidylate Synthase Inhibitors in the Treatment of Advanced Colorectal Cancer: Current Status

Abstract

The combination of 5-fluorouracil (5-FU) and leucovorin has been the unofficial "standard" therapy for patients with colorectal cancer for over a decade. Recently, however, a number of new agents targeted against the enzyme thymidylate synthase have been synthesized and are in various stages of development. The currently available thymidylate synthase inhibitors are discussed.Enormous efforts have been made over the years to improve the efficacy of 5-FU, the most popular of these agents. Biochemical modulation by leucovorin has been the most successful so far. Continuous infusion schedules also appear to be advantageous over bolus administration. However, marked intra-and interpatient variability, combined with nonlinear elimination kinetics and erratic oral bioavailability are relative limitations to further development of 5-FU. New oral 5-FU prodrugs such as UFT, S-1, and Capecitabine may help to overcome some of these difficulties. Eniluracil, a potent inhibitor of the enzyme dihydropyrimidine dehydrogenase, may also help by overcoming potential 5-FU resistance mechanisms, in addition to increasing its bioavailability. Of the antifolate-based inhibitors, Tomudex is in the most advanced stage of development. Similar efficacy with 5-FU and a convenient schedule may suggest a role in future combination regimens.It is quite likely that even the most optimal thymidylate synthase inhibition will have limitations in terms of clinical efficacy. Novel combinations of 5-FU or its analogs with agents that have different mechanisms of action (e.g., oxaliplatin, irinotecan) could provide important new opportunities for improving the outlook of patients with colorectal cancer.

Slow-Cycling Therapy-Resistant Cancer Cells

“…It appears likely that subsets of tumor cells evade initial chemotherapy and survive to repropagate the tumor [3,4]. Traditional chemotherapies like 5-fluorouracil (5-FU) and Oxaliplatin require active cycling cells to trigger cell death [4,5]. Cells that are quiescent or cycling slowly are therefore less likely to be susceptible to these drugs, suggesting an inherent recurrence mechanism in which slow-cycling cells evade therapeutic agents and repropagate tumors.…”

Gene expression in colorectal cancer and in vitro chemosensitivity to 5‐fluorouracil: A study of 88 surgical specimens

“…Novel combinations of 5-FU or its analogs with agents that have different mechanisms of action (e.g., oxaliplatin, irinotecan) could provide important new opportunities for improving the outlook for patients with colorectal cancer. 4) When a meta-analysis was conducted on nine randomized clinical trials that compared 5-FU with 5-FU plus intravenous LV in patients with advanced colorectal cancer, 5-FU plus LV showed a highly significant benefit over 5-FU alone in terms of tumor response rate, but this increase in response did not result in a discernable improvement in overall survival. However, a large number of patients did not respond to treatment in both groups.…”

A “combination oligonucleotide” antisense strategy to downregulate thymidylate synthase and decrease tumor cell growth and drug resistance

“…2,3 The TS inhibitors 5-fluorouracil (5-FU) and raltitrexed (ZD1694, Tomudex s ) have become integral drugs in standard treatments for colorectal cancer. 4 Although reasonably successful in clinical treatment of human tumors, use of these drugs is limited by their toxicity to nontumor cells and development of treatment resistance. These limitations drive the search for alternative treatments.…”