Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics.

Abstract

We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.

Noninvasive quantitation of cytosine deaminase transgene expression in human tumor xenografts with in vivo magnetic resonance spectroscopy

“…Namely, the failure to produce images of CD activity occurred because there was minimal entrapment of 18 F-labeled FNuc products in tumor cells during the period of imaging. Our results also are consistent with previous clinical MRS studies demonstrating a significant association between the intratumoral half-life of 5-FU and therapeutic response (43)(44)(45).…”

Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium‐DTPA‐enhanced MRI and localized 19F MRS pharmacokinetic studies of 5‐fluorouracil

“…In contrast, in previous clinical studies the trapping of FU has been related to therapy outcome (14,54,55). In a group of 57 patients with various primary tumor types a partial response was achieved in eight out of nine patients who exhibited a half-life for FU in tumor of more than 20 min (14).…”

Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture

“…It follows, therefore, that this radiation-enhancing effect involves increased radiosensitivity of S-phase cells and/or disruption of dsDNA break repair mechanism facilitated by FdUMP (2). Another interesting possibility is that radiation treatment before 5-FC incubation enhanced intracellular 5-FU retention and subsequently increased its tumor-killing capacity (31). Increased enhancement of the effects of radiation with prolonged exposure to 5-FC likely reflects increased tumor cell exposure to 5-FU and its metabolites.…”