13542 Background: Since the advent of various novel (molecular target) agents, it has been inevitable to reassure the dose regimen of 5-FU, a key drug in CRC. Recently, we have achieved good clinical benefits and cost-effectiveness in the treatment of CRC using ‘Pharmacokinetic Modulating Chemotherapy (PMC)’, which was designed as a hybrid of lower continuous (metronomic) and higher shorter plasma 5-FU concentration (Cancer 89: 1228, 2000, Cancer Res 61:1029, 2001, Proc ASCO 22: 1175, 2003). To establish a safer and more efficacious dose and scheduling of 5-FU administration from the perspective of cell cycle regulation, we investigated their anti-tumor efficiency by dose-enhancement and drug holidays, and the adverse events. Methods: First, weekly PMC regimens with or without dose-intensification and drug holidays were designed according to the mathematical model, and, then, experimented on the cell growth in vitro. Secondly, we assessed the clinical effects of the PMC regimens between “Tsunami 7” without drug holidays and “Tsunami 5” with a 2-day break (d 5–6) before a 1-day intensification (d 7), in Dukes’ B or C CRC patients (n=179), by the end-points of adverse events and 5-yr disease-free survival (DFS). Results: Adding 24-hr pharmacokinetic modulation by higher-dose intensification to the existing lower continuous (metronomic) formula succeeded in abrogation of the cell cycle block, leading to a nip in the steady tumor growth in vitro. Furthermore, setting of drug holidays seemed to change the cell cycle in favor of maximization of the targeted fraction. The clinical outcome of “Tsunami 5” regimen showed a tendency of less adverse events and improved 5-yr DFS than that of “Tsunami 7” (85% vs 75%, P=0.113). Conclusions: These results suggest that weekly 5-FU administration with a 2-day break before a 1-day intensification can be acceptable as an outpatient clinic first- line option because of reduced adverse events and maintained efficacy. Availability of efficacious chemotherapy reproduced by only oral agents (e.g. fluoropyrimidine, and leucovorin) mimicking the pharmacokinetics in this cell-cycle-oriented dose-dense “Tsunami” regimen would be beneficial for many cancer patients. No significant financial relationships to disclose.