Optimizing Chemotherapy Dose Using 31P NMR Spectroscopy

使用 31P NMR 波谱优化化疗剂量

• 批准号: 7013706
• 负责人: JASON Arthur KOUTCHER
• 金额: $ 22.16万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013706
• 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（由申请方提供）：广泛的临床前研究表明，肿瘤ATP消耗超过85%可增强肿瘤对标准细胞毒性抗肿瘤药物的反应。这种增强的反应是用显著较低剂量的抗肿瘤剂获得的。建议的ATP和嘧啶消耗方案包括3种药物，6-甲巯基嘌呤核苷（MMPR），6-氨基烟酰胺（6AN）和N-（膦酰基）-L-天冬氨酸（PALA）。虽然MMPR和PALA已在临床上组合，但尚未确定6 AN与PALA和MMPR组合的最佳生物活性剂量。已知6AN抑制糖酵解和戊糖磷酸途径，其在生物化学上通过肿瘤中ATP的减少和6-磷酸葡萄糖酸盐（6PG）的增加来表现。在本申请中，我们建议使用临床31 P核磁共振（NMR）光谱监测给药后的肿瘤代谢，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去耦31 P NMR光谱检测6PG和NTP（核苷三磷酸）的变化，以响应临床相关剂量的6AN（和PALA，MMPR）。NTP的变化和6PG的检测将决定6AN的生物活性剂量。我们将a）定量确定6-AN剂量递增对NTP和SPG变化的影响，B）确定6-AN（具有固定剂量的MMPR和PALA）与紫杉醇组合作为NTP消耗策略的最佳剂量，c）在确定6-AN的最佳剂量后，确定紫杉醇与MMPR、PALA和6-AN组合的最大耐受剂量（MTD）。我们将确定外周血单核细胞中6PG的测量值是否是测量肿瘤中6PG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的定量测量与肿瘤反应之间的关系。假设NTP降低> 50%和存在峰面积与其他检测到的代谢物（如磷酸胆碱（PC）或磷酸乙醇胺（PE））相当（>50%）的6PG是诱导应答所必需的。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。