P-31 MRS: CHEMOTHERAPY RESPONSE PREDICTOR

本申请的主要目的是批判性地评估 体内31 P MRS提供肿瘤预测标志物的潜力 治疗前和/或治疗后早期对化疗的反应 “测试”剂量（即，最大耐受剂量的一部分）。 因为 MRS是非破坏性的，在这些研究中开发和评估的方法 使用明确定义的鼠肿瘤模型的研究可应用于 诊所 化疗的临床预测因子的可用性 选择一个更有效的，个性化的 疗法 一个特别强调的是放在识别标志，这两个 对肿瘤的治疗反应具有特异性，对临床敏感， 相关的“试验”剂量。 化疗的反应特异性标志物 来自三个主要类别的代理（即，DNA结合剂嵌入剂， 烷化剂和抗代谢物）和一种新的抗肿瘤剂， 未知的机制将通过使用包含以下内容的肿瘤组来识别 一个肿瘤对每种药物明显敏感， 无论是先天的还是诱导的抵抗力。为了确定哪个，如果 在初始治疗前存在肿瘤的任何31 P MRS代谢特征 治疗是对化疗反应的预测标志物， 敏感和耐药肿瘤中存在的特征将是 比较了 确定31 P MRS代谢的哪些变化（如果有） 对“试验”剂量化疗剂的反应特征 提供了反应的预测标志， 在敏感和耐药肿瘤中观察到的特征将是 比较了 为了确定治疗后的最早时间， 将采集明显的31 P MRS代谢特征数据 在肿瘤发生前及肿瘤发生后1h、5.5h、10 h、24 h及24 h， 质量减少50%或重新生长。 既检查剂量- 这种变化的响应关系，并确定最小剂量 需要引起这些变化，动物接受剂量的 将观察到80%最大耐受剂量（MTD）、50% MTD或25% MTD 在治疗前和治疗后的最早时间， 观察变化，直至肿瘤质量减少50%或 再生

The main objective of this application is to evaluate critically the potential for in vivo 31P MRS to provide predictive markers of tumor response to chemotherapy before and/or early after treatment with a "test" dose (i.e., a fraction of the maximum tolerated dosage). Because MRS is nondestructive, the methodology developed and evaluated in these studies, using well-defined murine tumor models, can be applied in the clinic. Availability of a clinical predictor of chemotherapeutic response would allow selection of a more effective, individualized therapy. A special emphasis is place on identifying markers which are both specific to a therapeutic response in tumors and sensitive to clinically- relevant "test" doses. Response-specific markers for chemotherapeutic agents from three major classes (i.e., DNA-binder-intercalators, alkylating agents and antimetabolites) and a new antitumor agent of unknown mechanism will be identified by using sets of tumors that contain one tumor clearly sensitive to each agent as well as counterparts with either innate or induced resistance to that agent. To determine which, if any, 31P MRS metabolic characteristics of tumors present prior to initial treatment are predictive markers of response to chemotherapy, those characteristics present in the sensitive and resistant tumors will be compared. To determine which, if any, changes in the 31P MRS metabolic characteristics in response to a "test" dose of chemotherapeutic agent provide predictive markers of response, the changes in those characteristics observed in the sensitive and resistant tumors will be compared. To determine the earliest time after treatment any change are evident in the 31P MRS metabolic characteristics data will be acquired prior to and 1h, 5.5h, 10h, 24h, and ever 24h thereafter until the tumor mass either is reduced by 50% or regrows. To both examine the dose- response relationship of such changes and determine the minimum dose required to elicit those changes, animals treated with doses of either 80% maximum tolerated dosage (MTD), 50% MTD or 25% MTD will be observed by 31P MRS prior to and from the earliest time after treatment such changes were noted until the tumor mass either is reduced by 50% or regrows.