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

Citation
Rw. Klecker et Jm. Collins, Thymidine phosphorylase as a target for imaging and therapy with thymine analogs, CANC CHEMOT, 48(5), 2001, pp. 407-412
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
5
Year of publication
2001
Pages
407 - 412
Database
ISI
SICI code
0344-5704(200111)48:5<407:TPAATF>2.0.ZU;2-A
Abstract
Purpose: Thymidine phosphorylase (TPase; platelet-derived endothelial cell growth factor) is an attractive target for imaging and therapy because of t he strong relationship between its expression in tumor biopsies and clinica l outcome in many tumor types. Although the mechanism has yet to be explain ed, expression of TPase is highly associated with angiogenesis. Methods: Tu mor 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 an d incorporated into DNA. Results: Preferential localization was found in ce lls with high TPase, e.g. U937. Incorporation was enhanced in cells with hi gh TPase by coincubation with modulators such as deoxyuridine. Conclusions: 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 di agnosis and during maneuvers intended to manipulate TPase. If the 5-X-Ura m olecules were labeled with a therapeutic isotope, e.g. I-125 or At-211, sel ective cytotoxicity would be expected in cells with high TPase expression. However, direct evaluation of the safety in vivo of the therapeutic approac h is required. The 5-X-Ura compounds constitute a novel approach to both im aging and therapy directed towards TPase. Further, there are distinct advan tages to using the imaging mode to identify tumors likely to benefit from t herapy with the same set of molecules.