Biomodulation of capecitabine by docetaxel in non-small*

描述(申请人提供)：晚期肺癌患者的预后很差，中位生存期不到12个月，这表明显然需要更有效的治疗。虽然氟嘧啶类药物不常用于非小细胞肺癌的治疗，但这些药物在辅助治疗环境中已显示出存活率的改善。最近推出的口服氟嘧啶卡培他滨对非小细胞肺癌的评估很有趣，因为它与紫杉醇或多西紫杉醇联合使用具有协同作用，紫杉醇或多西紫杉醇是治疗非小细胞肺癌最活跃的药物之一。这种协同作用被认为是由于胸苷磷酸化酶(TP)的上调，该酶负责卡培他滨对肿瘤的优先激活。我们开发了一种新的联合应用多西紫杉醇和卡培他滨的方案，该方案考虑了多西紫杉醇上调TP的时间依赖性。这个时间表的目的是提供TP的重复刺激，并在预测的最大TP上调时间给予卡培他滨。使用这个时间表，我们展示了以前接受化疗的非小细胞肺癌患者的活性。对一组患者肿瘤块中TP、二氢嘧啶脱氢酶(DPD)和胸苷合成酶(TS)表达的评估表明，TP肿瘤与正常和TP/DPD比值以及肿瘤核TS可能是预测治疗反应的有用指标。 我们建议在以前没有接受化疗的非小细胞肺癌患者中研究这种联合/方案。肿瘤和正常肺组织将被评估对这种联合反应的潜在预测因素。此外，将测量外周单核细胞中的DPD活性，以建立与DPD正态分布内的毒性的关系。 这项拟议的研究有可能为晚期非小细胞肺癌确定一种新的联合治疗方法，并提供一种预测性方法来确定患者对联合治疗的反应更容易接受。对我们的工作假说的确认可能会导致一种新的治疗范例，适用于佐剂环境下的评估。

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.