Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines.
Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines.
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DOI：
10.1038/sj.bjc.6601011
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发表时间：
2003-06-16
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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吉西他滨（2′，2 ′-二氟脱氧胞苷）是一种脱氧胞苷类似物，可被脱氧胞苷激酶（dCK）活化为单磷酸，随后活化为三磷酸dFdCTP，掺入RNA和DNA中，导致DNA损伤。多药耐药（MDR）的特征是膜外排泵P-糖蛋白（P-gP）或多药耐药相关蛋白（MRP）的过度表达。吉西他滨针对人黑色素瘤、非小细胞肺癌、小细胞肺癌、表皮样癌和卵巢癌细胞进行了测试，这些细胞具有MDR表型，这是通过药物暴露或用mdr 1基因转染进行选择的结果。这些细胞系对吉西他滨的敏感性是其亲本细胞系的9至72倍。多柔比星耐药细胞2 R120（MRP 1）和2 R160（P-gP）对吉西他滨的敏感性分别是其亲本SW 1573细胞的9倍和28倍（P<0.01），25 μM维拉帕米可完全逆转这种敏感性。在2 R120和2 R160细胞中，dCK活性分别是SW 1573的7倍和4倍，这与dCK mRNA和dCK蛋白的增加有关。在2 R120和2 R160中，脱氧胞苷脱氨酶的灭活作用分别降低了2.9倍和2.2倍。在0.1 μM吉西他滨作用24 h后，SW 1573及其MDR变异体中dFdCTP的积累相似，但dFdCTP在2 R120（P<0.001）和2 R160（P<0.003）细胞中的保留时间更长。2 R120和2 R160细胞也分别将4倍和6倍多的[3 H]吉西他滨掺入DNA中（P<0.05）。P-糖蛋白和MRP 1过表达可能引起细胞应激，导致吉西他滨代谢和敏感性增加，而维拉帕米逆转附带的吉西他滨敏感性也表明膜外排泵的存在与吉西他滨敏感性之间存在直接关系。
Gemcitabine (2′,2′-difluorodeoxycytidine) is a deoxycytidine analogue that is activated by deoxycytidine kinase (dCK) to its monophosphate and subsequently to its triphosphate dFdCTP, which is incorporated into both RNA and DNA, leading to DNA damage. Multidrug resistance (MDR) is characterised by an overexpression of the membrane efflux pumps P-glycoprotein (P-gP) or multidrug resistance-associated protein (MRP). Gemcitabine was tested against human melanoma, non-small-cell lung cancer, small-cell lung cancer, epidermoid carcinoma and ovarian cancer cells with an MDR phenotype as a result of selection by drug exposure or by transfection with the mdr1 gene. These cell lines were nine- to 72-fold more sensitive to gemcitabine than their parental cell lines. The doxorubicin-resistant cells 2R120 (MRP1) and 2R160 (P-gP) were nine- and 28-fold more sensitive to gemcitabine than their parental SW1573 cells, respectively (P<0.01), which was completely reverted by 25 μM verapamil. In 2R120 and 2R160 cells, dCK activities were seven- and four-fold higher than in SW1573, respectively, which was associated with an increased dCK mRNA and dCK protein. Inactivation by deoxycytidine deaminase was 2.9- and 2.2-fold decreased in 2R120 and 2R160, respectively. dFdCTP accumulation was similar in SW1573 and its MDR variants after 24 h exposure to 0.1 μM gemcitabine, but dFdCTP was retained longer in 2R120 (P<0.001) and 2R160 (P<0.003) cells. 2R120 and 2R160 cells also incorporated four- and six-fold more [3H]gemcitabine into DNA (P<0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity.
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影响因子：
5.8
作者：
Bergman, AM;Munch-Petersen, B;Peters, GJ
通讯作者：
Peters, GJ
影响因子：
8.4
作者：
Bergman, AM;Giaccone, G;Peters, GJ
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Peters, GJ
影响因子：
5
作者：
Bergman, AM;Pinedo, HM;Peters, GJ
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Peters, GJ
影响因子：
8.8
作者：
Beck, J;Bohnet, B;Brügger, D;Bader, P;Dietl, J;Scheper, RJ;Kandolf, R;Liu, C;Niethammer, D;Gekeler, V
通讯作者：
Gekeler, V
影响因子：
8.8
作者：
Jensen, PB;Holm, B;Sorensen, M;Christensen, IJ;Sehested, M
通讯作者：
Sehested, M