Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells
Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells
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DOI：
10.1007/s00210-005-1080-4
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发表时间：
2005-07-01
影响因子：
3.6
通讯作者：
Gut, I
中科院分区：
文献类型：
--
作者：
Ehrlichova, M;Vaclavikova, R;Gut, I
肿瘤对经典紫杉烷类（紫杉醇和多西他赛）的耐药性在化疗中存在问题。因此，合成了在耐药肿瘤中具有更高抗肿瘤活性的新紫杉烷。本研究比较了紫杉醇和多西他赛与新型紫杉烷SB-T-1103、SB-T-1214和SB-T-1216在阿霉素敏感（MDA-MB-435）和耐药（NCI/ADR-RES）人乳腺癌细胞中的细胞毒性和转运。检查的细胞系在阿霉素转运方面不同，表明ABC膜转运蛋白的不同表达。逆转录-聚合酶链反应显示，NCI/ADR-RES细胞表达高水平的P-糖蛋白mRNA，这在MDA-MB-435细胞中是不存在的，而MRP 2 mRNA则相反。这两种细胞系共享或不同地表达其他八个ABC转运蛋白和LRP。在MTT测定中，NCI/ADR-RES细胞对紫杉醇的抗性是MDA-MB- 435细胞的1，000倍，对多西他赛的抗性是MDA-MB- 435细胞的600倍，但对SB-T-1103、SB-T-1214和SB-T-1216的敏感性几乎相同。这符合NCI/ADR-RES细胞吸收的[C-14]紫杉醇几乎是MDA-MB-435细胞的1/20，多西他赛大约是MDA-MB-435细胞的1/7，以及几乎等量的SB-T-1103、SB-T-1214和SB-T-1216的事实。维拉帕米使NCI/ADR-RES细胞对[C-14]紫杉醇的摄取增加7倍，使其外排减少2.5倍;相反，它对MDA-MB-435细胞的摄取影响很弱，并增加了外排。SB-T-1103和SB-T-1216不影响紫杉醇的转运，但SB-T-1214降低了两种细胞系中的[C-14]紫杉醇摄取，表明摄取抑制。这表明新的紫杉烷类不是P-糖蛋白的抑制剂。然而，新型紫杉烷类化合物对耐药肿瘤细胞的活性远高于经典紫杉烷类化合物，似乎是治疗紫杉烷耐药肿瘤的潜在药物。
The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin- sensitive (MDA-MB-435) and - resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P- glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA- MB- 435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [C-14] paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [C-14] paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [C-14] paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.