Thymidine phosphorylase as a target for imaging and therapy with thymine analogs.

Abstract

Thymidine phosphorylase (TPase; platelet-derived endothelial cell growth factor) is an attractive target for imaging and therapy because of the strong relationship between its expression in tumor biopsies and clinical outcome in many tumor types. Although the mechanism has yet to be explained, expression of TPase is highly associated with angiogenesis. Tumor cells were phenotyped for TPase activity, and incubated with thymine or its analogs (5-X-Ura). After intracellular conversion to thymidine analogs via the reverse reaction for TPase, these molecules were phosphorylated and incorporated into DNA. Preferential localization was found in cells with high TPase, e.g. U937. Incorporation was enhanced in cells with high TPase by coincubation with modulators such as deoxyuridine. 5-X-Ura molecules can be readily labeled with positron emitters, and this finding provides support for further evaluation in vivo of their potential as probes for noninvasive external imaging of TPase, both at the time of diagnosis and during maneuvers intended to manipulate TPase. If the 5-X-Ura molecules were labeled with a therapeutic isotope, e.g. 125I or 211At, selective cytotoxicity would be expected in cells with high TPase expression. However, direct evaluation of the safety in vivo of the therapeutic approach is required. The 5-X-Ura compounds constitute a novel approach to both imaging and therapy directed towards TPase. Further, there are distinct advantages to using the imaging mode to identify tumors likely to benefit from therapy with the same set of molecules.