Barret Jean-Marc, Kruczynski Anna, Etiévant Chantal, Hill Bridget T
Division de Cancérologie, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81100 Castres, France.
Cancer Chemother Pharmacol. 2002 Jun;49(6):479-86. doi: 10.1007/s00280-002-0451-5. Epub 2002 Apr 6.
F 11782, or 2',3'-bis-pentafluorophenoxyacetyl-4',6'-ethylidine-beta- D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin 2 N-methyl glucamine salt, a novel dual catalytic inhibitor of topoisomerases I and II, characterized by marked antitumour activity in vivo in a series of experimental murine and human tumours, has been selected for further development. This preclinical study was undertaken to investigate its potential for inclusion in combination chemotherapy regimens. The in vitro cytotoxicity of F 11782 incubated simultaneously with the following drugs was investigated: aclarubicin, cisplatin, doxorubicin, etoposide, 5-fluorouracil, mitomycin C, paclitaxel, topotecan or vinorelbine.
The combinations were first evaluated in vitro against the GCT27 human testicular teratoma cell line and then against the A549 human non-small cell lung cancer cell line using median effect analysis.
F 11782 in combination with cisplatin, mitomycin C, etoposide or doxorubicin showed synergistic cytotoxicity against both cell lines. Moreover, F 11782 combined with cisplatin or mitomycin C showed antitumour activity in vivo against P388 murine leukaemia grafted intravenously. Such synergy might have resulted from the identified nucleotide excision repair inhibitory activity of F 11782.
F 11782 appears to be a promising candidate for combination chemotherapy, especially with DNA-damaging agents.
F 11782，即4'-磷酸-4'-二甲基表鬼臼毒素2 N-甲基葡甲胺盐的2'，3'-双五氟苯氧基乙酰基-4'，6'-亚乙基-β-D-葡萄糖苷，一种新型的拓扑异构酶I和II双重催化抑制剂，在一系列实验性小鼠和人类肿瘤中表现出显著的体内抗肿瘤活性，已被选定进行进一步开发。本临床前研究旨在探讨其纳入联合化疗方案的潜力。研究了F 11782与以下药物同时孵育时的体外细胞毒性：阿柔比星、顺铂、多柔比星、依托泊苷、5-氟尿嘧啶、丝裂霉素C、紫杉醇、拓扑替康或长春瑞滨。
首先使用中位效应分析在体外对GCT27人睾丸畸胎瘤细胞系进行评估，然后对A549人非小细胞肺癌细胞系进行评估。
F 11782与顺铂、丝裂霉素C、依托泊苷或多柔比星联合使用时，对两种细胞系均表现出协同细胞毒性。此外，F 11782与顺铂或丝裂霉素C联合使用时，对静脉移植的P388小鼠白血病具有体内抗肿瘤活性。这种协同作用可能源于F 11782已确定的核苷酸切除修复抑制活性。
F 11782似乎是联合化疗的一个有前景的候选药物，特别是与DNA损伤剂联合使用时。
