This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aboagye, E. O. Articles by Price, P. M. Search for Related Content PubMed PubMed Citation Articles by Aboagye, E. O. Articles by Price, P. M.

Extraction of 5-Fluorouracil by Tumor and Liver

A Noninvasive Positron Emission Tomography Study of Patients with Gastrointestinal Cancer¹

Cancer Research Campaign Positron Emission Tomography Oncology Group, Department of Cancer Medicine, Imperial College School of Medicine [E. O. A., A. S., P. M. P.], and Medical Research Council Cyclotron Unit [V. J. C., S. O.], Hammersmith Hospital, London W12 0NN, United Kingdom

Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[¹⁸F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K_I = 0.0033 ± 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K_I = 0.7313 ± 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66–91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94–98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.

This article has been cited by other articles:

				N. Gupta, A. Saleem, B. Kotz, S. Osman, E. O. Aboagye, R. Phillips, C. Vernon, H. Wasan, T. Jones, P. J. Hoskin, et al. Carbogen and Nicotinamide Increase Blood Flow and 5-Fluorouracil Delivery but not 5-Fluorouracil Retention in Colorectal Cancer Metastases in Patients. Clin. Cancer Res., May 15, 2006; 12(10): 3115 - 3123. [Abstract] [Full Text] [PDF]

				P. Workman, E. O. Aboagye, Y.-L. Chung, J. R. Griffiths, R. Hart, M. O. Leach, R. J. Maxwell, P. M. J. McSheehy, P. M. Price, and J. Zweit Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst, May 3, 2006; 98(9): 580 - 598. [Abstract] [Full Text] [PDF]

				J. R. Bading, P. B. Yoo, J. D. Fissekis, M. M. Alauddin, D. Z. D'Argenio, and P. S. Conti Kinetic Modeling of 5-Fluorouracil Anabolism in Colorectal Adenocarcinoma: A Positron Emission Tomography Study in Rats Cancer Res., July 1, 2003; 63(13): 3667 - 3674. [Abstract] [Full Text] [PDF]

				A. Saleem, G. D. Brown, F. Brady, E. O. Aboagye, S. Osman, S. K. Luthra, A. S. O. Ranicar, C. S. Brock, M. F. G. Stevens, E. Newlands, et al. Metabolic Activation of Temozolomide Measured in Vivo Using Positron Emission Tomography Cancer Res., May 15, 2003; 63(10): 2409 - 2415. [Abstract] [Full Text] [PDF]

				B. Keith, X.-D. Guo, S. Zentko, N. Harold, B. Schuler, M. Quinn, J. Shapiro, and J. L. Grem Impact of Two Weekly Schedules of Oral Eniluracil Given with Fluorouracil and Leucovorin on the Duration of Dihydropyrimidine Dehydrogenase Inhibition Clin. Cancer Res., May 1, 2002; 8(5): 1045 - 1050. [Abstract] [Full Text] [PDF]

				G. N. Filippova, C.-F. Qi, J. E. Ulmer, J. M. Moore, M. D. Ward, Y. J. Hu, D. I. Loukinov, E. M. Pugacheva, E. M. Klenova, P. E. Grundy, et al. Tumor-associated Zinc Finger Mutations in the CTCF Transcription Factor Selectively Alter Its DNA-binding Specificity Cancer Res., January 1, 2002; 62(1): 48 - 52. [Abstract] [Full Text] [PDF]