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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase
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Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase

机译：对靶向二氢叶酸还原酶和胸苷酸合酶的药物的耐药性的新方面

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Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the model system to study 5-fluorouracil (5-FU) resistance. In leukemias, we and others have shown that transport, efflux, polyglutamylation and hydrolase activities are major determinants of MTX resistance. We have further reported that some leukemic cells have an increase in DHFR gene copy number possibly contributing to the resistant phenotype. Recently, we have begun to study in detail the molecular mechanisms that govern translational regulation of DHFR in response to MTX as an additional resistance mechanism. Studies thus far involving colorectal tumors obtained from patients have focused predominantly on the predictive value of levels of TS expression and p53 mutations in determining response to 5-FU. Although the predictive value of these two measures appears to be significant, given the variety of resistance to 5-FU observed in cell lines, it is not likely that these are the only measures predictive of response or responsible for acquired resistance to this drug. The enzyme uridine-cytidine monophosphate kinase (UMPK) is an essential and rate-limiting enzyme in 5-FU activation while dihydropyrimidine dehydrogenase (DPD) is a catabolic enzyme that inactivates 5-FU. Alterations in UMPK and DPD may therefore explain failure of 5-FU response in the absence of alterations in TS or p53. Transcription factors that regulate TS may also influence drug sensitivity. We have found that mRNA levels of the E2F family of transcription factors correlates with TS message levels and are higher in lung metastases than in liver metastases of colorectal cancers. Moreover, gene copy number of the E2F-1 gene appears to be increased in a significant number of samples obtained from metastases of colorectal cancer. We have also generated mutants of both DHFR and TS that confer resistance to MTX as well as 5-FU by random as well as site-directed mutagenesis. These mutants used alone or as fusion cDNAs of the mutants have proven to be useful in transplant studies where transfer of these mutant cDNAs to bone marrow cells have been shown to confer drug resistance to recipients. The fusion cDNAs of DHFR such as the DHFR-herpes simplex virus type 1 thymidine kinase (HSVTK) are also useful for regulation of gene expression in vivo using MTX as the small molecule regulator that can be monitored by positron emission tomography (PET) scanning or by optical imaging using a fusion construct such as DHFR-EGFP.
机译：耐药性通常是成功化疗的限制因素。我们的实验室对研究针对胸苷酸生物合成途径的药物，特别是针对胸苷酸合酶（TS）和二氢叶酸还原酶（DHFR）的药物的耐药机制感兴趣。我们已经使用白血病作为模型系统来研究对甲氨蝶呤（MTX）的耐药性，并将大肠癌作为模型系统来研究5-氟尿嘧啶（5-FU）的耐药性。在白血病中，我们和其他人已表明转运，外排，多聚谷氨酰化和水解酶活性是MTX耐药性的主要决定因素。我们进一步报道了一些白血病细胞的DHFR基因拷贝数增加，可能有助于耐药表型。最近，我们已经开始详细研究控制DHFR响应MTX的翻译调控的分子机制，这是一种额外的抗性机制。迄今为止，涉及从患者获得的结直肠肿瘤的研究主要集中于TS表达和p53突变水平在确定对5-FU反应中的预测价值。尽管考虑到在细胞系中观察到的对5-FU的耐药性，这两种措施的预测值似乎很重要，但这些措施不可能是唯一预测反应或对这种药物产生耐药性的措施。尿苷-胞苷单磷酸激酶（UMPK）是5-FU激活中必不可少的限速酶，而二氢嘧啶脱氢酶（DPD）是使5-FU失活的分解代谢酶。因此，在没有TS或p53改变的情况下，UMPK和DPD的改变可以解释5-FU反应失败。调节TS的转录因子也可能影响药物敏感性。我们已经发现，E2F转录因子家族的mRNA水平与TS信息水平相关，并且在肺转移中比在大肠癌的肝转移中更高。此外，在从结肠直肠癌转移获得的大量样品中，E2F-1基因的基因拷贝数似乎增加了。我们还产生了DHFR和TS的突变体，它们通过随机以及定点诱变赋予对MTX和5-FU的抗性。这些突变体单独使用或用作突变体的融合cDNA已被证明可用于移植研究，在移植研究中，已证明这些突变cDNA向骨髓细胞的转移可赋予受体以耐药性。 DHFR的融合cDNA（例如DHFR-疱疹病毒1型胸苷激酶（HSVTK））也可用于通过MTX作为小分子调节剂在体内调节基因表达，可通过正电子发射断层扫描（PET）扫描或通过使用融合构建体（例如DHFR-EGFP）进行光学成像。

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