P-31 MRS: CHEMOTHERAPY RESPONSE PREDICTOR

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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.