Synergistic Cytotoxic Effect of Combined Nucleoside/Base Analogs
Topics in This Section
5-Fluorouracil (5-FU) is one of the most widely used anti-cancer drugs, particularly for colorectal cancer with a greatest impact. The mechanism of 5-FU activity involves three cellular effects: (1) inhibition of thymidylate synthase; (2) incorporation of 5-FU into DNA; and (3) incorporation of 5-FU into RNA.
A nucleoside analog of 5-FU is also a potent anticancer drug, known to have cytotoxic effects in eukaryotic cells. Its administration to culture cells or laboratory animals results in its incorporation into DNA. However, no extensive studies with this compound have been published on its ability to act as a chemotherapeutic.
Dr. Yoshihiro Matsumoto has found that the combination of 5-FU with a nucleoside analog caused a synergistic level of cell killing that is far beyond the one expected from the additive effect of two drugs. 5-FU at a concentration of 0.5 µM inhibited growth of HT-29 cells (a colon cancer cell line with mutant p53) less than 10%, while the second drug at 5 µM did not inhibit more than 10% cell growth. In contrast, when the two drugs are combined, cell growth was inhibited by 80%. Similar synergisitic effects were observed with HCT116 (a colon cancer cell line with wild-type p53), Panc-1 (a pancreatic cancer cell line) and EKVX cells (a lung cancer cell line).
Dr. Yoshihiro Matsumoto's approach is to employ 5-FU for helping another cytotoxic drug to generate massive DNA damage in the replication-dependent manner. Thus, this strategy will generate a new line of 5-FU based combinational cancer therapies.
- Anti-cancer drug
Commercial and research use licenses to intellectual property are available.
Toxicity in-vivo data available
- Grem JL, "5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development," Healthcare Cost and Utilization Project," Invest New Drugs (2000); 18(4): 299-313.
- Longley DB, Harkin DP, et al., "5-fluorouracil: mechanisms of action and clinical strategies," Nat Rev Cancer (2003); 3(5): 330-8
- O'Connors OA,"Pharmacological Moldulation of Fluoropyrimidines: Building on the Lessons of the Past in Cancer Drug Discovery and Development: Combination Cancer Therapy: Modulators and Potentiators," (Schwartz GK ed); pp 133-174; Humana Press Inc.; Totowa, NJ (2005)
U.S. Patent pending.