In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation.
In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation.
复制标题
DOI：
10.1038/sj.bjc.6603970
复制
发表时间：
2007-10-08
影响因子：
8.8
通讯作者：
Ciccolini, J.
中科院分区：
文献类型：
--
作者：
Fanciullino, R.;Giacometti, S.;Mercier, C.;Aubert, C.;Blanquicett, C.;Piccerelle, P.;Ciccolini, J.
耐药性是癌症化疗治疗失败的主要原因，包括广泛使用的抗代谢药5-氟尿嘧啶（5-FU）。在这项研究中，我们试图通过使用双重打击策略来逆转5-FU耐药性：将5-FU与生化调节剂结合以改善其肿瘤活化，并将这两种药物包封在同一个隐形脂质体中。在高度耐药的典型SW 620人结直肠模型中进行的实验显示，当这些细胞用我们的脂质体制剂处理时，对5-FU的敏感性高达80%。使用该制剂的结果表明，肿瘤药物摄取增加30%，活性代谢物增加（包括关键的5-氟-2-脱氧尿苷-5-单磷酸）的活化更好，肿瘤胸苷酸合酶的上级抑制（98%），以及随后的早期和晚期细胞凋亡的诱导更高。药物监测显示，脂质体制剂给药大鼠的暴露量较高且持续。当在异种移植动物模型中检查时，我们的双药剂脂质体制剂引起肿瘤大小减少74%，平均存活时间增加一倍，而标准5-FU未能表现出显著的抗增殖活性以及增加荷瘤小鼠的寿命。总的来说，我们的数据表明，耐药性5-FU可以克服通过更好地控制其肿瘤内激活和使用胶囊制剂。
Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (5-FU). In this study, we tried to reverse 5-FU resistance by using a double-punch strategy: combining 5-FU with a biochemical modulator to improve its tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation.
登录
查看更多内容
影响因子：
8.8
作者：
Evrard, A;Cuq, P;Ciccolini, J;Vian, L;Cano, JP
通讯作者：
Cano, JP
影响因子：
11.5
作者：
Boyer, J;McLean, EG;Johnston, PG
通讯作者：
Johnston, PG
影响因子：
8.8
作者：
Fracasso, PM;Blum, KA;McLeod, HL
通讯作者：
McLeod, HL
DOI：
10.1073/pnas.88.24.11460
发表时间：
1991-12-01
影响因子：
11.1
作者：
PAPAHADJOPOULOS, D;ALLEN, TM;MARTIN, FJ
通讯作者：
MARTIN, FJ
影响因子：
11.5
作者：
Blanquicett, C;Saif, MW;Johnson, MR
通讯作者：
Johnson, MR