CLINICAL STUDIES

临床研究

• 批准号: 3771679
• 负责人: JOSEPH Rocco BERTINO
• 金额: --
• 依托单位: ST. VINCENT CATHOLIC MEDICAL CTR NURSING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3771679
• 关键词: N phosphonoacetyl L aspartate; antineoplastics; biopsy; bone marrow; breast neoplasms; clinical trials; colon neoplasms; combination cancer therapy; dosage; doxorubicin; drug interactions; drug screening /evaluation; fluorouracil; glucuronates; high performance liquid chromatography; human subject; human therapy evaluation; leucovorin; neoplasm /cancer pharmacology; pancreas neoplasms; sarcoma; stomach neoplasms; uridine

The purpose of this clinical research is to extend to treatment of cancer patients concepts and specific drug regimens that have produced significant increases in therapeutic effectiveness in tumor-bearing mice. These regimens were developed on the basis of specific biochemical interactions of the several drugs contained therein. The initial focus is upon the modulation of the effects of 5-fluorouracil (FUra) by N- phosphonacetyl-L-aspartate (PALA), which depletes intracellular pyrimidine pools, and methylmercaptopurine ribonucleoside (MMPR) or methotrexate, which enhance phosphorylation of FUra by increasing cellular content of phosphoribosyl pyrophosphate (PRPP), and uridine for "rescue" from the toxicity of FUra. Two specific regimens will be studied which produced a significant increase in FUra effect in mice. These are PALA + MMPR + FUra, and PALA + MTX + leucovorin + uridine rescue. The major focus is on an ATP-depleting triple combination of PALA-MMPR-6-AN which effected regressions in murine tumors. Greater tumor-regressing effects were obtained by the addition of Fura or Adriamycin to the triple chemotherapy. Clinical protocols evaluate these regimens on advanced cancers of the colon, breast, pancreas, stomach and sarcomas. Concomitant with exploring dose tolerance and therapeutic effect of the regimens in patients, we will measure the effect that the modulating dose drugs have upon the content of PRPP, ATP NAD, UTP, and 6-phosphogluconate in biopsies of accessible tumors and normal bone marrow. These studies assess the biochemical changes as guidelines to the dosage (s) to be employed clinically as well as whether or not the changes are selective. By means of these studies, we hope not only to improve the therapy of patients with cancer, but also to establish a mechanism for examining the metabolic changes produced by the agents in patients. An understanding of these metabolic changes may facilitate patient care, as well as indicate biochemical loci in human tumors that may be subject to further manipulation.

这项临床研究的目的是扩展到癌症的治疗 患者的概念和具体的药物治疗方案产生了 显着提高荷瘤小鼠的治疗效果。 这些方案是根据特定的生化指标制定的。 其中包含的几种药物的相互作用。 最初的焦点 是通过 N- 调节 5-氟尿嘧啶 (FUra) 的作用 膦乙酰基-L-天冬氨酸 (PALA)，可消耗细胞内的 嘧啶库和甲硫基嘌呤核糖核苷 (MMPR) 或 甲氨蝶呤，通过增加 FUra 的磷酸化 磷酸核糖焦磷酸 (PRPP) 和尿苷的细胞含量 “拯救”FUra 的毒性。 两种具体方案将 研究表明，这可显着增加小鼠体内的 FUra 效应。 它们是 PALA + MMPR + FUra 和 PALA + MTX + 亚叶酸 + 尿苷 救援。 主要焦点是消耗 ATP 的三重组合 PALA-MMPR-6-AN 影响小鼠肿瘤的消退。 更大 通过添加 Fura 或 Fura 获得了肿瘤消退效果 阿霉素予三联化疗。 临床方案评估这些 治疗晚期结肠癌、乳腺癌、胰腺癌、胃癌和 肉瘤。 同时探索剂量耐受性和治疗 治疗方案对患者的效果，我们将测量治疗方案的效果 调节剂量药物对 PRPP、ATP、NAD、UTP 和 可及肿瘤和正常骨活检中的 6-磷酸葡萄糖酸盐 骨髓。 这些研究评估生化变化作为指导 临床上使用的剂量以及是否 改变是有选择性的。 通过这些研究，我们不仅希望 改善癌症患者的治疗，同时也建立一个 检查药物产生的代谢变化的机制 患者。 了解这些代谢变化可能有助于 患者护理，以及指出人类肿瘤中的生化位点 可能会受到进一步的操纵。