MODULATION OF [5-I-125]IODODEOXYURIDINE INCORPORATION INTO TUMOR AND NORMAL TISSUE DNA BY METHOTREXATE AND THYMIDYLATE SYNTHASE INHIBITORS

A potentially useful method for imaging of micrometastases and in situ radiotherapy, would be the incorporation of radioactive labelled iodo deoxyuridine (IdU) into tumour DNA. However, there are two main proble ms: incorporation of the radioactive IdU into normal cells and low inc orporation into tumour cells. The aim of this study was to attempt to augment the incorporation of [5-I-125] iododeoxyuridine ((125)IdU) int o tumour DNA and to improve the tumour/normal tissue ratio by the use of inhibitors (methotrexate, 5-fluorouracil, AG337, ZD 1694, benzyloxy benzyl uracil) which would prolong the metabolic half-life of the comp ound. Mammary tumours were induced in GR mice, which were then treated with the inhibitors and the (125)IdU. The tumours and representative normal tissue were removed following sacrifice of the animals, and rad ioactivity within the tissues measured. Pretreatment of mammary carcin oma-bearing GR mice with methotrexate caused approximately a 3-fold in crease in the incorporation of (125)IdU into tumour DNA, and approxima tely a greater than or equal to 10-fold increase in the tumour/small i ntestine ratio of incorporated radioactivity. Inhibition of thymidylat e synthase, the enzyme involved in IdU dehalogenation, by 5-fluorourac il plus folic acid, or by novel inhibitors AG337 and ZD1694 led to a 3 - to 5-fold increase in the (125)IdU incorporation. Benzyloxybenzyl ur acil, an inhibitor of dihydrouracil dehydrogenase, had little effect. Treatment of tumour-bearing mice with methotrexate plus ZD1694 signifi cantly reduced the rate of tumour growth, but addition of (125)IdU (70 mu Ci/mouse, three daily injections) had no additional antitumour act ivity. In conclusion, these results do not support the hypothesis that systemic administration of (125)IdU can be used for cancer therapy or for imaging purposes unless better methods are found to boost its inc orporation into tumour DNA. Copyright (C) 1996 Elsevier Science Ltd