Molecular mechanisms of sequence-dependent antitumor effects of SN-38 and 5-fluorouracil combination therapy against colon cancer cells.

BACKGROUND The aim of this study was to clarify the molecular mechanisms of the sequence-dependent antitumor activity of SN-38 and 5-fluorouracil (5-FU) against colon cancer cells. MATERIALS AND METHODS KM12SM and HCT116 colon cancer cells were exposed to 5-FU and/or SN-38 in various conditions. The nature of interactions was determined by median-effect analysis. Cell cycle, apoptosis, and expression of thymidylate synthase (TS) were analyzed. RESULTS A strong synergism was observed after initial sequential exposure of SN-38, and the activity was enhanced by a 24 h-interval to the drug-exposure. Antagonism was observed after low-dosage initial sequential exposure of 5-FU. Low-dosage 5-FU caused G(2) arrest and high-dosage 5-FU caused G(1) arrest. TS protein level significantly decreased after exposure to SN-38. CONCLUSION The sequence dependency between SN-38 and 5-FU against colon cancer cells may be related to the dual action on cell cycle regulation by 5-FU and to the down-regulation of TS level by SN-38.