Optimizing Chemotherapy Dose Using 31P NMR Spectroscopy

描述(由申请人提供)：广泛的临床前研究表明，肿瘤ATP耗竭超过85%可以增强肿瘤对标准细胞毒性抗肿瘤药物的反应。这种增强的反应是在显著较低剂量的抗肿瘤药物下获得的。该方案包括3种药物：6-甲基硫代嘌呤核苷、6-氨基烟酰胺和N-(膦-乙酰基)-L-天冬氨酸。虽然MMPR和PALA已在临床上联合应用，但6AN与PALA和MMPR联合应用的最佳生物活性剂量尚未确定。已知6AN抑制糖酵解和磷酸戊糖途径，这在生化上表现为肿瘤中ATP的减少和6-磷酸葡萄糖酸(6PG)的增加。在这一应用中，我们建议使用临床31P核磁共振(31P核磁共振)谱来监测6AN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。具体地说，我们将使用1H去耦合31P核磁共振波谱来检测6PG和NTP(核苷三磷酸盐)在临床相关剂量下对6AN(以及PALA、MMPR)的响应变化。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6AN剂量递增对NTP和SPG变化的影响，b)确定6-AN(与固定剂量的MMPR和PALA)作为NTP消耗策略的最佳剂量，c)在确定6-AN的最佳剂量后，确定紫杉醇联合MMPR、PALA和6-AN的最大耐受量(MTD)。我们将确定外周血单核细胞中6PG的测量是否可以替代6PG的肿瘤测量，并预测6AN在肿瘤中的活性。我们还将确定NTP、6PG的定量测量与肿瘤反应的关系。据推测，NTP&gt；50%的减少以及峰面积与其他检测到的代谢物(如磷胆碱(PC)或磷乙醇胺(PE))相当的6PG的存在将是诱导反应所必需的。这些研究中确定的剂量将允许对这一战略进行进一步的第二阶段研究。如果外周血淋巴细胞中6PG的测量与肿瘤6PG相关，未来的研究将不需要进一步的核磁共振研究。

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.