Purpose: To improve the therapeutic efficacy and minimize the toxicity of 5-fluorouracil (5-FU), intermittent therapy consisting of alternate 24-h intravenous infusion and based on differences in generation time (T(G)) between normal cells and tumor cells was investigated.
Methods: Two human gastric cancer cell lines MKN-7 and MKN-74 with T(G) of 35 h and 17 h, respectively, were used in an in vitro cytotoxic assay. The drug exposure schedule consisted of a continuous 144-h exposure and alternate 24-h exposures. In a clinical trial, a total of 23 patients with advanced or recurrent gastric cancer were treated with intermittent therapy consisting of 24-h intravenous infusion with 5-FU 700 mg/m(2) per day on days 1, 3 and 5 in combination with low-dose cisplatin (CDDP) at 3.3 mg/m(2) per day on days 1 to 5. One cycle of the combined chemotherapy lasted for four consecutive weeks, followed by withdrawal over 1-2 weeks. Plasma 5-FU concentrations were measured by high-performance liquid chromatography in 15 patients and dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMC) was measured in 13 patients.
Results: The in vitro study revealed no statistically significant difference in cytotoxicity of 5-FU between the two drug exposure schedules in MKN-7 cells. In MKN-74 cells, however, a statistically significant decrease in cytotoxicity was found with the alternate 24-h exposure. In a clinical trial, plasma 5-FU concentrations showed a trapezoidal pattern. There was a significant correlation between DPD activity in PBMC and total body clearance of 5-FU. There were eight partial responders (8/22, 36%). Toxicities were very mild in severity, with no grade 3 or 4 toxicity. In particular, diarrhea and stomatitis were infrequent (one patient), and none of the patients developed thrombocytopenia.
Conclusions: Toxicities which may be observed in rapidly growing cells such as bone marrow cells and gastrointestinal epithelial cells following continuous intravenous infusion of 5-FU seemed to be reduced by intermittent therapy of 5-FU consisting of alternate 24-h intravenous infusions.