PHARMACOLOGY OF ANTICANCER AGENTS

这个项目的总体目标是勾勒出 口腔癌治疗中的药代动力学和药效学。的确有 强有力的证据表明5-FU的药代动力学是一个主要决定因素 口腔癌患者对5-FU诱导化疗的反应。 类似地，二氢嘧啶脱氢酶的胞内活性 5-磷酸脱氢酶(DPD)和胸苷合成酶(S)，这两种酶对5-磷酸脱氢酶有贡献。 FU合成代谢和分解代谢分别被认为是 5-氟尿嘧啶诱导反应和毒性的重要性 化疗。然而，诱导化疗还没有被证明是有效的。 在大型随机研究中对这些患者的总体存活率的影响。 另一方面，伴随的放化疗已经被证明是 延长生存期和无病生存期。迄今为止，阿司匹林的药代动力学研究 5-氟尿嘧啶或其他药物没有在这种情况下进行检查。的目标是 这个项目是为了阐明药代动力学的可能贡献。 对伴随性药物临床试验结果参数的影响 放化疗。我们将致力于将药代动力学与 阿司匹林治疗晚期口腔癌患者的疗效和生存率 三种临床方案并建立数学模型进行优化 在随后的临床试验中对个别患者进行剂量测定。我们还将 试图将DPD和TS活性与5-FU药代动力学相关联， 临床毒性、反应和生存。我们将寻求将DPD与 外周血单个核细胞(PBMC)活性及其活性 以验证PBMC作为替代组织的使用。 最近，DPD抑制剂乙炔基尿嘧啶已被开发为一种 5-氟尿嘧啶调节剂。乙炔尿嘧啶的联合用药 使用5-FU会导致5-FU半衰期大大延长，从而增加 静脉推注或口服后全身暴露于药物 它们也可能增加5-FU的细胞毒性。我们将探索 乙炔尿嘧啶对5-FU药代动力学和药效学的贡献 在放化疗研究中(仅使用口服给药 毒品)。DPD活性将在化疗前和白天进行测定 4研究该调节剂对乙炔基尿嘧啶的影响 肿瘤和外周血单核细胞DPD活性。与这项研究相一致的是 血尿嘧啶浓度分析。我们希望这些 研究将教我们如何在理性的 时尚进入诊所，目标是提高治愈率 最大限度减少口腔放化疗的临床毒性 癌症。

The overall objective of this project is to delineate the role of pharmacokinetics and -dynamics in the therapy of oral cancers. There is strong evidence that 5-FU pharmacokinetics represent a major determinant of response to 5-FU-based induction chemotherapy in oral cancers. Similarly, intracellular activities of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (S), the major enzymes contributing to 5- FU anabolism and catabolism, respectively, have been implicated to be of importance for response and toxicity of 5-FU-based induction chemotherapy. However, induction chemotherapy has not been shown to impact on overall survival of these patients in large randomized studies. Concomitant chemoradiation therapy on the other hand has been shown to prolong survival and disease-free survival. To date, pharmacokinetics of 5-FU or other-drugs have not been examined in this setting. The goal of this project is to elucidate a possible contribution of pharmacokinetics to outcome parameters in clinical trials of concomitant chemoradiotherapy. We will aim at correlating pharmacokinetics with response and survival in patients with advanced oral cancer treated on three clinical protocols and establish mathematical models to optimize dosing in individual patients on subsequent clinical trials. We will also attempt to correlate DPD and TS activity with 5-FU pharmacokinetics, clinical toxicity, response and survival. We will seek to correlate DPD activity in peripheral blood mononuclear cells (PBMC) with its activity in tumor tissues to verify the use of PBMC's as surrogate tissue. Recently, the DPD inhibitor, ethynyluracil, has been developed as a modulator of 5-FU. The administration of ethynyluracil in combination with 5-FU results in a much prolonged 5-FU half-life thus increasing systemic exposure to the drug following its IV-bolus or oral administration; they may also increase 5-FU cytotoxicity. We will explore the contribution of ethynyluracil to 5-FU pharmacokinetics and -dynamics in chemoradiotherapy studies (using exclusively orally administered drugs). DPD activity will be determined prior to chemotherapy and at day 4 following ethynyluracil to study the impact of this modulator on tumoral and PBMC DPD activity. Coincident with this study will be an analysis of plasma uracil concentrations. It is our hope that these studies will teach us how to introduce new 5-FU modulators in a rational fashion into the clinic with the goal of increasing cure rates while minimizing the clinical toxicity resulting from chemoradiotherapy of oral cancer.