Biomodulation of capecitabine by docetaxel in non-small*

描述（申请人提供）：晚期肺癌患者预后不良，中位生存期不到12个月，表明明显需要更有效的治疗。虽然氟尿嘧啶不常用于治疗NSCLC，但这些药物已证明在辅助治疗中可改善生存率。最近引入的口服氟嘧啶卡培他滨在NSCLC中的评价令人感兴趣，因为其与紫杉醇或多西他赛（NSCLC治疗中最有效的药物之一）联合使用具有协同潜力。这种协同作用被认为是由于胸苷磷酸化酶（TP）的上调，其负责卡培他滨的优先肿瘤活化。我们开发了一种新的多西他赛和卡培他滨联合治疗方案，该方案考虑了多西他赛上调TP的时间依赖性。该方案旨在提供TP的重复刺激，并在预测的TP最大上调时间给予卡培他滨。使用该方案，我们证明了对既往接受过化疗的NSCLC的活性。TP，二氢嘧啶脱氢酶（DPD）和胸苷酸合成酶（TS）的表达从一组这些患者的肿瘤块的评价表明，TP肿瘤正常和TP/DPD的比率，以及肿瘤核TS，可能是有用的预测因子的反应，以治疗。 我们建议在既往未接受过化疗的NSCLC患者中研究这种联合/方案。将评价肿瘤和正常肺组织对该组合反应的潜在预测因子。此外，将测量外周单核细胞中的DPD活性，以确定DPD正态分布内与毒性的关系。 拟议的研究有可能确定一种新的晚期NSCLC联合治疗，并提供一种预测方法，以确定更适合联合治疗的患者。我们的工作假设的确认可能会导致一个新的治疗模式，适合在辅助设置的评估。

DESCRIPTION (provided by applicant): The poor prognosis of patients with advanced lung cancer, with a median survival of less than 12 months, indicates an obvious need for more effective treatments. Although fluoropyrimidines are not commonly used to treat NSCLC, these agents have demonstrated improvements in survival in the adjuvant setting. The recently introduced oral fluoropyrimidine capecitabine is interesting for evaluation in NSCLC, given its synergistic potential in combination with paclitaxel or docetaxel, drugs that are among the most active in the treatment of NSCLC. This synergy is believed due to upregulation of the enzyme thymidine phosphorylase (TP), which is responsible for the preferential tumor activation of capecitabine. We have developed a novel schedule for the combination of docetaxel and capecitabine that takes into consideration the time dependency of TP upregulation by docetaxel. This schedule is aimed to provide for repetitive stimulation of TP, and for capecitabine administration at the predicted times of maximal TP upregulation. Using this schedule, we demonstrated activity in NSCLC previously treated with chemotherapy. Evaluation of TP, dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) expression m tumor blocks from a group of these patients suggested that TP tumor to normal and TP/DPD ratios, as well as tumor nuclear TS, may be useful as predictors of response to treatment. We propose to study this combination/schedule in NSCLC patients not previously treated with chemotherapy. Tumor and normal lung tissue will be evaluated for potential predictors of response to this combination. In addition, DPD activity in peripheral mononuclear cells will be measured to establish relationships to toxicity within the DPD normal distribution. The proposed research has the potential of identifying a new combination treatment for advanced NSCLC and providing a predictive approach to identify patients more amenable to treatment response to the combination. Confirmation of our working hypothesis may lead to a new treatment paradigm suitable for evaluation in the adjuvant setting.