5-fluorouracil (5-FU) is a key drug for colorectal cancer (CRC) despite the advent of various novel molecular target agents. Recently, we have achieved good clinical results 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: 1228-1235, 2000, Cancer Res 61:1029-1037, 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 in vitro and clinically, and the adverse events clinically.
Materials and 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 growth of three human colorectaladenocarcinoma cell lines, HCT116 (wild-type p53), SW480 and HCT116/p53mut (mutant p53), by flow cytometry, laser scanning cytometry, and analysis of cell-cycle-related proteins. Secondly, we assessed the clinical effects of the PMC regimens between “PMC7” without drug holidays and “PMC5” with a 2-day break (day 5-6) before a 1-day intensification (day 7), in CRC patients, by the end-points of adverse events and three-year disease-free survival.
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 “PMC5” regimen showed significantly less adverse events than that of “PMC7” and equivalent disease-free survival.
Conclusion: These results suggest that chemotherapeutic efficiency can be enhanced by ingenious contrivance of dose and schedule exploiting cell cycle checkpoint regulation. Weekly 5-FU administration with a 2-day break before a 1-day intensification can be recommended as an outpatient clinic first-line regimen because of reduced adverse events and maintained cytotoxic efficacy.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA