Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Curr Pharm Des. 2012;18(19):2811-29. doi: 10.2174/138161212800626175.
Gemcitabine is one of the most widely used pyrimidine analogues, with a well-established role as a first- and second-line treatment of several types of tumors. Several preclinical and clinical studies have been done to obtain information on molecular determinants of gemcitabine activity and metabolism, in order to predict whether this drug will be effective and safe for the individual patient. Among these molecular determinants, the mRNA and protein expression of equilibrative transporter-1 (ENT1) and ribonucleotide reductase (RR) emerged as possible predictors of drug activity in studies on pancreatic and non-small cell lung cancer. However, cytidine deaminase polymorphisms and activity were correlated with clinical outcome and severe toxicities, whereas further studies should evaluate both P53 dependent and independent pathways involved in gemcitabine induced apoptosis. Improved knowledge on these determinants is critical for the optimal development of combination of gemcitabine with other conventional or biological therapies, as well as to exploit the radiosensitizing potential of gemcitabine. Emerging technologies such as massive parallel sequencing, gene expression arrays and proteomics may identify novel biomarkers in tumor material, while polymorphisms and phenotyping analysis should unravel factors involved in drug toxicity. Validation of these markers in preclinical models should be used for the appropriate patient enrolment into subsequent prospective studies. Hopefully, novel pharmacogenetic biomarkers will be validated in these prospective studies and used to select cancer patients to be treated with gemcitabine-based regimens in the near future or to enroll them in studies with prodrugs in order to bypass resistance mechanisms.
吉西他滨是最广泛使用的嘧啶类似物之一，在几种类型的肿瘤的一线和二线治疗中具有明确的作用。已经进行了几项临床前和临床研究，以获取关于吉西他滨活性和代谢的分子决定因素的信息，以便预测该药物对个体患者是否有效和安全。在这些分子决定因素中，平衡转运蛋白-1（ENT1）和核糖核苷酸还原酶（RR）的 mRNA 和蛋白表达在胰腺癌和非小细胞肺癌的研究中作为药物活性的可能预测因子出现。然而，胞嘧啶脱氨酶多态性和活性与临床结果和严重毒性相关，而进一步的研究应评估参与吉西他滨诱导细胞凋亡的 P53 依赖性和非依赖性途径。这些决定因素的更好了解对于吉西他滨与其他常规或生物疗法联合的最佳开发至关重要，并且可以利用吉西他滨的放射增敏潜力。大规模平行测序、基因表达阵列和蛋白质组学等新兴技术可能会在肿瘤组织中识别出新型生物标志物，而多态性和表型分析应该阐明与药物毒性相关的因素。应在临床前模型中验证这些标志物，以便将这些患者纳入随后的前瞻性研究中。希望在这些前瞻性研究中验证新的药物遗传学生物标志物，并将其用于选择接受基于吉西他滨的方案治疗的癌症患者，或者将其纳入前药研究以绕过耐药机制。
