SEARCH FOR THE OPTIMAL SCHEDULE FOR THE OXALIPLATIN 5-FLUOROURACIL ASSOCIATION MODULATED OR NOT BY FOLINIC ACID - PRECLINICAL DATA/

The combination of oxaliplatin (LOHP)-5-fluorouracil (FU)-folinic acid (FA) has provided high response rates in pretreated patients with adv anced colorectal cancer that is resistant to FU-FA, However, the choic e of the optimal schedule between LOHP, FU, and FA remains open. The p urpose of the present study was to compare, at equivalent drug area un der the curve, different schedules for the LOHP-FU +/- FA combinations on four human colorectal cancer cell lines. FU +/- FA was tested as a 2-h short exposure (''bolus''), a 118-h continuous exposure (''infusi on''), or a 22-h mixed exposure (''De Gramont protocol''). LOHP was ad ministered for 2 h before, during, or after FU +/- FA exposure. Isobol ogram analyses revealed that LOHP associated with FU +/- FA resulted i n synergistic cytotoxic effects whatever the tested schedules (in grea ter than or equal to 75% of cases). For the FU-LOHP combination, cytot oxicity was significantly different according to the FU exposure type (short > mixed > continuous) and was independent of the LOHP position. In contrast, for the FU-FA-LOHP combination, neither the FU exposure type nor the LOHP position significantly influenced cytotoxicity. The presence of FA significantly enhanced the cytotoxicity of FU-LOHP (P < 0.001); this potentiation was independent of the FU exposure type and was significantly influenced by the LOHP position (LOHP after FU-FA > LOHP during FU-FA > LOHP before FU-FA). In conclusion, in contrast wi th the recognized superiority of continuous FU exposure over short exp osure when the drug is given alone, the FU-LOHP combination is more cy totoxic when FU is given as a short exposure. This suggests the potent ial interest of such a schedule in the clinical setting.