Poindessous Virginie, Koeppel Florence, Raymond Eric, Cvitkovic Esteban, Waters Stephen J, Larsen Annette K
Group of Biology and Pharmacogenetics of Human Tumors, CNRS UMR 8113, Ecole Normale Supérieure, Cachan and Institut Gustave-Roussy, Villejuif , France.
Int J Oncol. 2003 Nov;23(5):1347-55.
Irofulven (6-hydroxymethylacylfulvene, MGI-114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product obtained from the Omphalotus mushroom. Irofulven has demonstrated potent activity against a broad range of solid tumors in both cellular and xenograft models and has shown promising activity in clinical trials. To guide the clinical use of irofulven, the present study used the MTT viability assay to examine the cytotoxic effects obtained by combining irofulven with two other anticancer agents: cisplatin and 5-fluorouracil (5-FU). The study was carried out with HT-29 and HCT-116 colorectal and A2780 ovarian carcinoma cells as well as with their irofulven- (HT-29/IF2, HCT-116/IF27) or cisplatin-resistant (A2780/CP70) variants. The combinations showed strong sequence specificity. Simultaneous exposure to cisplatin and irofulven was at least additive for four cell lines including the cisplatin-resistant A2780/CP70 ovarian cells which exhibit a multifactorial resistance phenotype. Cisplatin followed by irofulven was additive for parental HCT-116 and A2780 cells whereas irofulven followed by cisplatin was antagonistic in all cellular models. Simultaneous exposure to 5-FU and irofulven was at least additive for all six cell lines. 5-FU followed by irofulven was additive for the parental HT-29 and A2780 cells and synergistic for the irofulven-resistant HCT-116 cell line. Irofulven followed by 5-FU was synergistic for the two ovarian cell lines and additive for the two parental colon cell lines. These studies demonstrate that simultaneous exposure to irofulven and cisplatin is at least additive for most cell lines whereas simultaneous exposure to irofulven and 5-FU is additive to synergistic for all the cell lines tested, including the irofulven- and cisplatin-resistant variants. The enhanced cytotoxicity of irofulven in combination with cisplatin and 5-FU support the clinical application of these regimens.
伊罗氟芬（6-羟甲基酰基富烯，MGI-114，NSC 683863）是从脐菇中获得的天然产物伊鲁丁S的半合成衍生物。伊罗氟芬在细胞模型和异种移植模型中均已显示出对多种实体瘤具有强大的活性，并且在临床试验中也显示出有前景的活性。为指导伊罗氟芬的临床应用，本研究使用MTT活力测定法来检测伊罗氟芬与另外两种抗癌药物顺铂和5-氟尿嘧啶（5-FU）联合使用时所产生的细胞毒性作用。该研究使用HT-29和HCT-116结肠癌细胞、A2780卵巢癌细胞以及它们的伊罗氟芬耐药（HT-29/IF2，HCT-116/IF27）或顺铂耐药（A2780/CP70）变体进行。这些联合用药显示出很强的顺序特异性。同时暴露于顺铂和伊罗氟芬对包括表现出多因素耐药表型的顺铂耐药A2780/CP70卵巢细胞在内的四种细胞系至少具有相加作用。先给予顺铂后给予伊罗氟芬对亲本HCT-116和A2780细胞具有相加作用，而先给予伊罗氟芬后给予顺铂在所有细胞模型中均具有拮抗作用。同时暴露于5-FU和伊罗氟芬对所有六种细胞系至少具有相加作用。先给予5-FU后给予伊罗氟芬对亲本HT-29和A2780细胞具有相加作用，而对伊罗氟芬耐药的HCT-116细胞系具有协同作用。先给予伊罗氟芬后给予5-FU对两种卵巢细胞系具有协同作用，而对两种亲本结肠细胞系具有相加作用。这些研究表明，同时暴露于伊罗氟芬和顺铂对大多数细胞系至少具有相加作用，而同时暴露于伊罗氟芬和5-FU对所有测试的细胞系（包括伊罗氟芬耐药和顺铂耐药变体）具有从相加到协同不等的作用。伊罗氟芬与顺铂和5-FU联合使用时增强的细胞毒性支持了这些治疗方案的临床应用。
