NOVEL TREATMENT OF REFRACTORY GI MALIGNANCIES

描述：（申请人摘要）本项目的总体目标 是为了测试高剂量的胃肠道外注射的羟基脲（HU） 合并到每周一次的高剂量氟尿嘧啶（5FU）方案中， 干扰素-α（IFN）和非格司亭（G）治疗难治性 胃肠道恶性肿瘤，并确定其影响， 调节体内核苷酸库的组合。 在体外 5FU + HU + IFN-α的组合协同抗2例人类 结肠癌细胞系，在临床上可达到的浓度。 这些试剂对mRNA影响的详细生物化学研究， 蛋白水平和活性的目标酶，核苷酸 还原酶（RR）和胸苷酸合成酶（TS）的活性 这证明了5FU + HU + IFN之间的正相互作用。 此外，采用高度敏感的DNA聚合酶测定， 测量对脱氧核糖核苷酸三磷酸（dNTPs）的影响， 体外和体内患者外周血单核细胞 （PBMC），并且已经证明了对嘌呤和嘧啶池的抑制。 基于这种有希望的体外数据，申请人最近 完成了高剂量5FU、HU和IFN加或减的I期试验 非格司亭（FHI-G），证明了该方案的耐受性。 本申请的具体目的是进行II期试验 FHI-G在胰腺、肝胆恶性肿瘤患者中的作用 系统和胃，并测量这种处理对游泳池的影响 的dNTPs。 申请人的I期试验使用了5FU，2.6 g/m2每周24小时输注+HU，4.3 g/m2每周48小时输注 + IFN-α，9 MU皮下注射，每周三次。 该剂量方案 非格司亭给药可耐受。 毒副反应主要为 血液学检查，疲劳、腹泻和口腔炎的程度可接受。 在胆道（1/2）、胃（5/8）和 胰腺癌（1/6）。 申请人打算延长其 之前的观察，通过使用FHI-G进行I期试验， 48小时HU输注+非格司亭，并描述联合治疗的效果 对dNTP池RR和TS的抑制，以试图预测谁将 对这样的待遇作出回应。

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.