The objective of this resubmitted application remain: to extend our noninvasive drug monitoring studies by generating data that would allow the monitoring, in individual breast cancer patients, of the biodistribution and the intratumoral metabolism of 5-Fluorouracil (5FU), a key drug used in the treatment of cancer, while that patient is undergoing chemotherapy (e.g, in real time). Our studies to date, monitoring the fate of 5FU using 19F-NMRS Spectroscopy (MRS), both in patients and in animal models, have revealed that 5FU is selectively trapped in some tumors, and such trapping is prognostic of a therapeutic response. The correlation between trapping of 5FU, given either alone or in combination with leucovorin, and clinical response, is statistically significant to p<.OOOl in a variety of human tumors, and that this test has shown to have 86% positive prediction, 100% negative prediction, a sensitivity (true positive) of 100%, a specificity (false positive) of 96%, and above all, not a single false negative. We now wish to continue documenting the potential clinical significance of these findings by highly focused experiments studying, noninvasively, the biodistribution, targeting and metabolism of 5FU in breast cancer patients. We propose to continue and expand our pilot work by analyzing the biodistribution and targeting and metabolism of 5FU in breast cancer patients when administered alone at conventional doses; alone, at higher than conventional doses; or after pretreatment with methotrexate. We will correlate the presence of trapped 5FU pools within the tumor with clinical response to 5FU plus leucovorin. We will continue studying the subtumoral heterogeneity of 5FU uptake and metabolism, attempt to measure the temporal distribution of tumoral 5FU between the tumor cell and the interstitial space, and enhance data acquisition by testing better sequences and various methods for absolute quantitation. Data analysis will continue using the radiopharmacokinetic approach. We believe that such detailed measurements of the molecular events that occur in human breast tumors during drug treatment may be an essential component of the knowledge require to develop novel strategies to optimize chemotherapy in breast cancer in general, as well as in providing guidance for the treatment of the specific patient in whom the presence (or the absence) of drug trapping has been established.
| Presant, C A; Wolf, W; Waluch, V et al. (2000) Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy. J Clin Oncol 18:255-61 |
| Wolf, W; Waluch, V; Presant, C A (1998) Non-invasive 19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies. NMR Biomed 11:380-7 |
| Wolf, W (1995) Imaging can be much more than pretty pictures. Pharm Res 12:1821-2 |
