P-31 MRS: CHEMOTHERAPY RESPONSE PREDICTOR

此应用程序的主要目标是批判性地评估 体内~(31)P MRS提供肿瘤预测标志物的可能性 在治疗前和/或治疗后早期对化疗的反应 “测试”剂量(即最大耐受量的一小部分)。因为 MRS是非破坏性的，在这些方面开发和评估的方法 使用定义明确的小鼠肿瘤模型的研究可以应用于 诊所。化疗临床预测指标的可用性 回应将允许选择更有效、更个性化的 心理治疗。 特别强调的是识别既具有 对肿瘤的治疗反应是特异的，对临床上- 相关的“测试”剂量。化疗中的反应特异性标志物 来自三个主要类别的试剂(即DNA-结合-嵌入剂， 烷化剂和抗代谢物)和一种新的抗肿瘤药物 未知的机制将通过使用包含以下内容的肿瘤集合来确定 一个肿瘤对每种药物以及对应的药物明显敏感 先天的或诱生的对该病原体的抗性。要确定哪一项，如果 在首次治疗前出现的肿瘤的任何，31P-MRS代谢特征 治疗是化疗反应的预测标志，那些 敏感和耐药肿瘤的特征将是 比较一下。以确定31P MRS代谢的哪些变化(如果有) 化疗药物对“试验”剂量的反应特征 提供响应的预测性标记，这些变化 在敏感和耐药肿瘤中观察到的特征将是 比较一下。要确定治疗后的最早时间有无变化 从31P MRS代谢特征数据中可以明显看出 直到肿瘤发生前和之后的1小时、5.5小时、10小时、24小时和曾经的24小时 质量要么减少50%，要么再生。既要检查剂量- 这种变化的反应关系及最小剂量的确定 需要引起这些变化的动物，用任何一种剂量的 将观察80%最大耐受量(MTD)、50%MTD或25%MTD 在治疗前和治疗后的最早时间通过31P MRS 直到肿瘤质量减少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.