Barret Jean-Marc, Etiévant Chantal, Baudouin Caroline, Skov Kirsten, Charvéron Marie, Hill Bridget T
Division de Cancéologie Centre de Recherche Pierre Fabre, Castres, France.
Anticancer Res. 2002 Jan-Feb;22(1A):187-92.
F 11782, or 2'', 3''-bispentafluorophenoxyacetyl-4, 6'-ethylidene-beta-D glucoside of 4'-phosphate-4'-dimethylepipodopliyllotoxin 2N-methyl glucamine salt, is a novel fluorinated lipophylic epipodophylloid which has shown marked antitumour activity in vivo. In vitro studies have demonstrated a dual catalytic inhibitory activity of F 11782 against topoisomerases and I and II by an original mechanism involving interference with the DNA binding activity of these enzymes, without DNA intercalating properties. Nevertheless, the precise mechanism(s) of cytotoxicity of F 11782 remains unclear and recent studies have suggested that this cytotoxicity might result, at least in part, from an induction of DNA-strand breaks without stabilisation of cleavable complex. In this study, DNA damage induced by F 11782 and its repair by non-homologous recombination was investigated in CHO-K1 cells. The results suggest that the nature of such damage differs from that induced by etoposide, a structurally-related topoisomerase II poison and identify a high level of stability of the damage induced which may account, at least in part, for the superior preclinical anti-tumour activity of F 11782.
F 11782，即4'-磷酸-4'-二甲基表鬼臼毒素2N-甲基葡糖胺盐的2'', 3''-双五氟苯氧基乙酰基-4, 6'-亚乙基-β-D-葡糖苷，是一种新型的氟化亲脂性表鬼臼毒素，已在体内显示出显著的抗肿瘤活性。体外研究表明，F 11782通过一种涉及干扰这些酶的DNA结合活性的原始机制，对拓扑异构酶I和II具有双重催化抑制活性，且不具有DNA嵌入特性。然而，F 11782细胞毒性的确切机制仍不清楚，最近的研究表明，这种细胞毒性可能至少部分是由DNA链断裂的诱导导致的，而可裂解复合物没有稳定化。在本研究中，研究了F 11782在CHO-K1细胞中诱导的DNA损伤及其通过非同源重组的修复。结果表明，这种损伤的性质与结构相关的拓扑异构酶II毒药依托泊苷诱导的损伤不同，并确定了所诱导损伤的高度稳定性，这可能至少部分解释了F 11782卓越的临床前抗肿瘤活性。
