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Intratumoral Conversion of 5-Fluorocytosine to 5-Fluorouracil by Monoclonal Antibody-Cytosine Deaminase Conjugates: Noninvasive Detection of Prodrug Activation by Magnetic Resonance Spectroscopy and Spectroscopic Imaging¹

The Johns Hopkins University School of Medicine, Department of Radiology, Oncology Section, Division of MR Research, Baltimore, Maryland 21205 (E. O. A., D. A., Z. M. B.), and Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121 (P. D. S.)

The monitoring of antibody-directed enzyme-prodrug therapies requires evaluation of drug activation within the tissues of interest. We have demonstrated the feasibility of noninvasive magnetic resonance spectroscopy and spectroscopic imaging (chemical shift imaging) to detect activation of the prodrug 5-fluorocytosine (5-FCyt) to the cytotoxic species 5-fluorouracil (5-FU) by monoclonal antibody-cytosine deaminase (CD) conjugates. In vitro, L6-CD but not 1F5-CD selectively metabolized 5-FCyt to 5-FU on H2981 human lung adenocarcinoma cells because of the presence and absence of cell surface L6 and CD20 antigens, respectively. After pretreatment of H2981 tumor-bearing mice with L6-CD, in vivo metabolism of 5-FCyt to 5-FU within the tumors was detected by ¹⁹F magnetic resonance spectroscopy; the chemical shift separation between 5-FCyt and 5-FU resonances was 1.2 ppm. 5-FU levels were 50–100% of 5-FCyt levels in tumors 10–60 min after 5-FCyt administration. Whole body ¹⁹F chemical shift imaging (6 x 6 mm in-plane resolution) of tumor-bearing mice demonstrated the highest signal intensity of 5-FU within the tumor region. This study supports further development of noninvasive magnetic resonance methods for preclinical and clinical monitoring of CD enzyme-prodrug therapies.

¹ Supported in part by USAMRMC Grant DAMD17-96-1-6131.

² To whom requests for reprints should be addressed, at Department of Radiology, MR Research, The Johns Hopkins University School of Medicine, 211 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205.

Received 6/ 9/98. Accepted 7/30/98.

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