Preclinical rationale for synergistic interaction of pemetrexed and cytotoxic nucleoside analogues.
Preclinical rationale for synergistic interaction of pemetrexed and cytotoxic nucleoside analogues.
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DOI：
10.3892/ol.2012.773
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发表时间：
2012-09
期刊：
影响因子：
2.9
通讯作者：
T. Oguri;H. Ozasa;T. Uemura;O. Takakuwa;E. Kunii;Daishi Kasai;H. Ohkubo;M. Miyazaki;K. Maeno;Shigeki Sato
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文献类型：
--
作者：
T. Oguri;H. Ozasa;T. Uemura;O. Takakuwa;E. Kunii;Daishi Kasai;H. Ohkubo;M. Miyazaki;K. Maeno;Shigeki Sato
细胞毒性核苷类似物广泛应用于癌症化疗。我们用胞嘧啶arabinoside （Ara-C）耐药的红白血病细胞系K562和Ara-C敏感的髓性白血病细胞系HL60检测分子标记的差异表达。我们发现脱氧胞苷激酶（dCK）和人平衡核苷转运蛋白1 （hENT1）的表达水平升高，而多药耐药蛋白5 （ABCC5）和核糖核苷还原酶亚基M1 （RRM1）的表达水平降低。我们之前建立了培美曲塞（MTA）耐药小细胞肺癌细胞系PC6/MTA-0.4和PC6/MTA-1.6，发现MTA耐药细胞对吉西他滨（GEM）和Ara-C比亲本PC-6细胞更敏感。我们检测了mta耐药细胞中GEM和Ara-C敏感性的分子标记，发现dCK和hENT1基因表达增加。此外，在Ara-C-耐药的K562细胞中，MTA处理导致dCK和hENT1的表达增加，ABCC5和RRM1的表达降低，同时改变了对Ara-C的抗性。这些结果证明MTA和细胞毒性核苷类似物联合使用的化疗活性在代谢分子的改变方面具有协同作用。
Cytotoxic nucleoside analogues are widely used in cancer chemotherapy. We used the cytosine arabinoside (Ara-C)-resistant erythroleukaemia cell line K562 and the Ara-C-sensitive myeloid leukaemia cell line HL60 to examine the differential expression of molecular markers. We found increased expression levels of deoxycytidine kinase (dCK) and human equilibrative nucleoside transporter 1 (hENT1) and decreased levels of multidrug resistance protein 5 (ABCC5) and ribonucleoside reductase subunit M1 (RRM1) expression in Ara-C-sensitive HL60 cells. We previously established the pemetrexed (MTA)-resistant small cell lung cancer cell lines PC6/MTA-0.4 and PC6/MTA-1.6 and found that MTA-resistant cells are more sensitive to gemcitabine (GEM) and Ara-C compared with parental PC-6 cells. We examined the molecular markers for GEM and Ara-C sensitivity in MTA-resistant cells and found increased gene expression of dCK and hENT1. Furthermore, treatment with MTA resulted in increased expression of dCK and hENT1 and decreased expression of ABCC5 and RRM1, concomitant with the alteration of the resistance to Ara-C in Ara-C-resistant K562 cells. These results provide evidence that the chemotherapeutic activity of the combination of MTA and cytotoxic nucleoside analogues is synergistic with regard to the alteration of metabolic molecules.