NOVEL TREATMENT OF REFRACTORY GI MALIGNANCIES

描述：(申请者摘要)本项目的总体目标 是为了测试一种大剂量的羟基尿素(HU)肠外输注 纳入大剂量氟尿嘧啶(5FU)的每周方案， 干扰素-α与非格列西汀联合治疗难治性白血病 胃肠道恶性肿瘤，并从生物化学的角度确定其影响 体内核苷酸库的调制组合。在体外， 5FU+HU+干扰素-α联合应用对2例人 结肠癌细胞株，在临床上可以达到的浓度。 这些药物对信使核糖核酸影响的详细生物化学研究， 靶标核糖核酸酶的蛋白质水平和活性 在体外进行还原酶(RR)和胸苷合成酶(TS)的测定 表明5FU+HU+干扰素之间存在正相互作用。 此外，高灵敏的dna聚合酶分析被用于 测量对脱氧核糖核酸三磷酸(DNTPs)的影响 患者外周血单个核细胞的体内外研究 (PBMC)，并表现出对嘌呤和嘧啶库的抑制作用。 基于这一有希望的体外数据，申请人最近 完成大剂量5FU、HU和干扰素加减的I期试验 非格列辛(FHI-G)，证明了该方案的耐受性。 本申请的具体目标是进行第二阶段试验 FHI-G在胰腺、肝胆恶性肿瘤患者中的检测 系统和胃，并测量这种治疗对泳池的影响 来自PBMC的dNTPs。申请人的一期试验使用了5FU，2.6 G/m2，每周24小时输液；HU，4.3 g/m2，每周48小时输液 +干扰素-α，9MU皮下注射，每周3次。这个养生法是 服用非格列西汀后可耐受。主要的毒副作用是 血液学，疲劳、腹泻和口腔炎的程度可以接受。 胆道反应(1/2)、胃反应(5/8)和 胰腺癌(1/6)。申请人打算延长他的 之前通过使用FHI-G进行第一阶段试验的观察 48小时HU输液+非格列西汀联合应用效果观察 抑制RR和TS对dNTP池的影响以尝试预测谁将 对这样的待遇做出反应。

DESCRIPTION: (Applicant's Abstract) The overall goals of this project are to test a high-dose parenteral infusion of hydroxyurea (HU) incorporated into a weekly regimen with high-dose fluorouracil (5FU), interferon-alpha (IFN) and filgrastim (G) in patients with refractory GI malignancies, and to determine the effects of this biochemically modulated combination of nucleotide pools in vivo. In vitro the combination of 5FU + HU + IFN-alpha was synergistic against 2 human colon cancer cell lines, at clinically achievable concentrations. Detailed biochemical studies of the effects of these agents on mRNA, protein levels and activity for the target enzymes, ribonucleotide reductase (RR) and thymidylate synthase (TS), were performed in vitro which demonstrated a positive interaction between 5FU + HU + IFN. Furthermore, a highly sensitive DNA polymerase assay was employed to measure the effects on deoxyribonucleotide triphosphates (dNTPs) both in vitro and in vivo in patient peripheral blood mononuclear cells (PBMC), and have demonstrated inhibition of purine and pyrimidine pools. Based on this promising in vitro data, the applicant has recently completed a Phase I trial of high-dose 5FU, HU and IFN plus or minus filgrastim (FHI-G) which demonstrated the tolerability of this regimen. The Specific Aims of this application are to conduct a Phase II trial of FHI-G in patients with malignancies of the pancreas, hepatobiliary system and stomach and to measure the effects of this treatment on pools of dNTPs from PBMC. The applicant's Phase I trial employed 5FU, 2.6 g/m2 as a 24h infusion weekly +HU, 4.3 g/m2 as a 48 h weekly infusion + IFN-alpha, 9 MU subcutaneously three times per week. This regimen was tolerable with administration of filgrastim. The major toxicities were hematologic, with acceptable levels of fatigue, diarrhea and stomatitis. Responses were observed in biliary tract (1/2), gastric (5/8) and pancreatic (1/6) carcinoma. The applicant intends to extend his previous observations by conducting a Phase I trial of FHI-G using the 48-hr HU infusion + filgrastim and delineate the effects of combined inhibition of RR and TS on pools of dNTPs to attempt to predict who will respond to such treatment.