Fischel J L, Etienne M C, Formento P, Milano G
Oncopharmacology Unit, Centre Antoine-Lacassagne, Nice, France.
Clin Cancer Res. 1998 Oct;4(10):2529-35.
The combination of oxaliplatin (LOHP)-5-fluorouracil (FU)-folinic acid (FA) has provided high response rates in pretreated patients with advanced colorectal cancer that is resistant to FU-FA. However, the choice of the optimal schedule between LOHP, FU, and FA remains open. The purpose of the present study was to compare, at equivalent drug area under 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 ("infusion"), or a 22-h mixed exposure ("De Gramont protocol"). LOHP was administered for 2 h before, during, or after FU +/- FA exposure. Isobologram analyses revealed that LOHP associated with FU +/- FA resulted in synergistic cytotoxic effects whatever the tested schedules (in > or = 75% of cases). For the FU-LOHP combination, cytotoxicity 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 with the recognized superiority of continuous FU exposure over short exposure when the drug is given alone, the FU-LOHP combination is more cytotoxic when FU is given as a short exposure. This suggests the potential interest of such a schedule in the clinical setting.
奥沙利铂（乐沙定，LOHP）-5-氟尿嘧啶（FU）-亚叶酸（FA）联合用药方案在对FU-FA耐药的晚期结直肠癌预处理患者中显示出较高的缓解率。然而，LOHP、FU和FA之间最佳给药方案的选择仍未确定。本研究的目的是在等效药时曲线下，比较LOHP-FU+/-FA联合用药在四种人结肠癌细胞系上的不同给药方案。FU+/-FA分别以2小时短时间暴露（“推注”）、118小时持续暴露（“输注”）或22小时混合暴露（“德格雷蒙方案”）进行测试。LOHP在FU+/-FA暴露前、暴露期间或暴露后给药2小时。等效线图分析显示，无论测试的给药方案如何，LOHP与FU+/-FA联合使用均产生协同细胞毒性作用（在≥75%的病例中）。对于FU-LOHP联合用药，细胞毒性根据FU暴露类型有显著差异（短时间暴露>混合暴露>持续暴露），且与LOHP给药位置无关。相比之下，对于FU-FA-LOHP联合用药，FU暴露类型和LOHP给药位置均未显著影响细胞毒性。FA的存在显著增强了FU-LOHP的细胞毒性（P<0.001）；这种增强作用与FU暴露类型无关，且受LOHP给药位置的显著影响（FU-FA后给药的LOHP>FU-FA期间给药的LOHP>FU-FA前给药的LOHP）。总之，与单独给药时持续FU暴露优于短时间暴露的公认优势相反，当FU短时间给药时，FU-LOHP联合用药具有更强的细胞毒性。这表明这种给药方案在临床环境中可能具有潜在价值。
