Optimizing Chemotherapy Dose Using 31P NMR Spectroscopy

使用 31P NMR 波谱优化化疗剂量

• 批准号: 7140177
• 负责人: JASON Arthur KOUTCHER
• 金额: $ 19.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140177
• 关键词: 6 thiopurine; N phosphonoacetyl L aspartate; adenosine triphosphate; aminopyridines; antineoplastics; bioassay; chemosensitizing agent; clinical research; clinical trials; combination chemotherapy; drug screening /evaluation; human subject; human therapy evaluation; lymphocyte; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; nucleoside triphosphate; paclitaxel; pentose phosphate shunt; pharmacokinetics; phosphorylcholine; pyrimidines; therapy design /development

DESCRIPTION (provided by applicant): Extensive pre-clinical studies have demonstrated that depletion of tumor ATP by greater than 85% can enhance tumor response to standard cytotoxic anti-neoplastic agents. This enhanced response is obtained with significantly lower doses of the anti-neoplastic agent. The proposed ATP and pyrimidine depleting regimen consists of 3 drugs, 6-methylmercaptopurine riboside (MMPR), 6-aminonicotinamide (6AN), and N-(phosphonacetyl)-L-aspartate (PALA). While MMPR and PALA have been combined clinically, the optimal biologically active dose of 6AN in combination with PALA and MMPR has not been determined. 6AN is known to inhibit glycolysis and pentose phosphate pathway which is manifested biochemically by a decrease in ATP and an increase in 6-phosphogluconate (6PG) in the tumor. In this application, we propose to use clinical 31P nuclear magnetic resonance (NMR) spectroscopy to monitor tumor metabolism after administration of 6AN to detect the biologically active dose of 6AN and evaluate clinical toxicity. Specifically, we will use 1H decoupled 31P NMR spectroscopy to detect 6PG and changes in NTP (nucleoside triphosphates) in response to 6AN (and PALA, MMPR) at clinically relevant doses. Changes in NTP and detection of 6PG will determine the biologically active dose of 6AN. We will a)determine quantitatively the effect of 6AN dose escalation on changes in NTP and SPG, b) determine the optimal dose of 6-AN (with a fixed dose of MMPR and PALA) as an NTP depleting strategy in combination with paclitaxel, c) after defining the optimal dose of 6-AN, determine the maximum tolerated dose (MTD) of paclitaxel in combination with MMPR, PALA, and 6-AN. We will determine if measurements of 6PG in peripheral blood mononuclear cells are a surrogate for measurement of tumor measurements of 6PG and predicts activity of 6AN in tumors. We will also determine the relationship between quantitative measurements of NTP, 6PG and tumor response. It is hypothesized that decreases in NTP > 50% and the presence of 6PG with a peak area comparable (>50%) to other detected metabolites (such as phosphocholine (PC) or phosphoethanolamine (PE)) will be necessary to induce responses. The doses determined in these studies, will allow further Phase II studies of this strategy. If measurements of 6PG in peripheral blood lymphocytes correlate with tumor 6PG, future studies would not require further NMR studies.

描述（由申请人提供）：广泛的临床前研究表明，肿瘤ATP的耗竭可以增强肿瘤对标准细胞毒性抗抑制剂的反应。通过明显较低的抗塑料剂剂量获得这种增强的反应。所提出的ATP和嘧啶耗尽方案包括3种药物，6-甲基二嘌呤核苷（MMPR），6-氨基氨基氨酸酰胺（6AN）和N-（磷酸乙酰基）-L-冬冬酸酯（PALA）。尽管MMPR和PALA在临床上已合并，但尚未确定6AN的最佳生物活性剂量与PALA和MMPR结合使用。已知6AN抑​​制糖酵解和五磷酸五磷酸途径，这在生化上通过ATP的降低和肿瘤中6-磷酸葡萄糖酸（6pg）的增加而表现出来。在此应用中，我们建议使用临床31p核磁共振（NMR）光谱法监测6AN给药后肿瘤代谢，以检测6AN的生物活性剂量并评估临床毒性。具体而言，我们将使用1H脱钩的31p NMR光谱法检测6pg，并在临床相关剂量下对6AN（和Pala，MMPR）的NTP（核苷三磷酸盐）的变化。 NTP的变化和6pg的检测将确定6AN的生物活性剂量。我们将a）定量确定6AN剂量升级对NTP和SPG变化的影响，b）确定6-AN（用MMPR和PALA固定剂量的MMPR和PALA）作为NTP耗竭策略与paclitaxel结合使用，与6-AN结合使用6-AN的最佳耐受剂量，并确定最大耐受剂量的最佳剂量（MMM）（MMM）（MMM）（MMM）（MMM）（MMM）（MMM）（MMM）（MM）。帕拉（Pala）和6个。我们将确定外周血单核细胞中6pg的测量是否是测量6pg肿瘤测量值的替代物，并预测肿瘤中6AN的活性。我们还将确定NTP，6pg和肿瘤反应的定量测量之间的关系。假设NTP> 50％的降低，并且与其他检测到的代谢产物（例如磷酸胆碱（PC）或磷酸乙醇胺（PE））相当的峰面积（> 50％）的6pg存在是诱导反应的。在这些研究中确定的剂量将允许对该策略进行进一步的II期研究。如果外周血淋巴细胞中6pg的测量与肿瘤6pg相关，则未来的研究将不需要进一步的NMR研究。