Modulation of [5-125I]iododeoxyuridine incorporation into tumour 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 iododeoxyuridine (IdU) into tumour DNA. However, there are two main problems: incorporation of the radioactive IdU into normal cells and low incorporation into tumour cells. The aim of this study was to attempt to augment the incorporation of [5-125I]iododeoxyuridine (125IdU) into tumour DNA and to improve the tumour/normal tissue ratio by the use of inhibitors (methotrexate, 5-fluorouracil, AG337, ZD 1694, benzyloxybenzyl uracil) which would prolong the metabolic half-life of the compound. Mammary tumours were induced in GR mice, which were then treated with the inhibitors and the 125IdU. The tumours and representative normal tissue were removed following sacrifice of the animals, and radioactivity within the tissues measured. Pretreatment of mammary carcinoma-bearing GR mice with methotrexate caused approximately a 3-fold increase in the incorporation of 125IdU into tumour DNA, and approximately a > or = 10-fold increase in the tumour/small intestine ratio of incorporated radioactivity. Inhibition of thymidylate synthase, the enzyme involved in IdU dehalogenation, by 5-fluorouracil plus folic acid, or by novel inhibitors AG337 and ZD1694 led to a 3- to 5-fold increase in the 125IdU incorporation. Benzyloxybenzyl uracil, an inhibitor of dihydrouracil dehydrogenase, had little effect. Treatment of tumour-bearing mice with methotrexate plus ZD1694 significantly reduced the rate of tumour growth, but addition of 125IdU (70 microCi/mouse, three daily injections) had no additional antitumour activity. In conclusion, these results do not support the hypothesis that systemic administration of 125IdU can be used for cancer therapy or for imaging purposes unless better methods are found to boost its incorporation into tumour DNA.
Mester
J
J
INSERM U55, 184, rue du Fauhourg St.-Antoine, Paris, France.
DeGoeij
K
K
Sluyser
M
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism*; D050744:Dihydrouracil Dehydrogenase (NAD+); D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D007065:Idoxuridine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007421:Intestine, Small / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011799:Quinazolines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D011799:Quinazolines; D013876:Thiophenes; C068991:5-benzyloxybenzyluracil; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D013940:Thymidylate Synthase; C068874:raltitrexed; C099178:nolatrexed; D007065:Idoxuridine; D005472:Fluorouracil; D008727:Methotrexate