Selective uptake of toxic nucleoside (125IUdR) by resistant cancer

We report uptake of a thymidine analogue 125-Iodine-5-iodo-2'-deoxyuridine (125IUdR) by nude mice bearing human xenografts of choriocarcinoma or colonic cancer. When 125IUdR was given alone, uptake by intestinal tissues was 5-10 times greater than by the tumours as measured by tissue gamma counting. This ratio was reversed when hydroxyurea or cytosine arabinoside were used as inhibitors of ribonucleotide reductase and were given in combination with 5-fluorouracil or methotrexate to inhibit thymidine synthesis shortly before injecting 125IUdR. Counting the radioactivity in tissues removed 24 hours after 125IUdR gave tumour to highest normal tissue ratios of up to 15:1, but the corresponding nuclear grain counts, which is probably a more reliable indicator of selective uptake into DNA, were in excess of 100:1. The addition of unlabelled IUdR to the regimen only reduced the uptake of 125IUdR when given in relatively large amounts. For this approach to be exploited it is concluded that the tumour must be resistant at the cell level to the inhibitor of DNA synthesis either de novo or as a result of prior exposure to it. This inhibitor can then be used to block uptake of the potentially toxic nucleoside analogue by normal renewal tissues while it is taken up by the resistant cancer cells. By inhibiting synthesis of the corresponding normal nucleosides with inhibitors to which the cancer cells are not resistant, incorporation of the toxic analogues into tumour DNA was enhanced. Although 125IUdR is a convenient agent for exploring this approach and is highly cytotoxic when incorporated in DNA, the clinical potential of reverse role chemotherapy probably lies with the development of toxic non-radioactive nucleoside analogues.