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UNLABELLED: We previously showed the tumor-targeting potential of the 125I-labeled thymidine analog 5-iodo-2'-deoxyuridine (IUdR) injected intratumorally in patients with high tumor-cell kinetics. In this study, we evaluated the tumor incorporation of [123I]IUdR infused intra-arterially in patients with liver metastases from colorectal cancer. METHODS: Iodine-123-IUdR (110-300 MBq, 3-8 mCi, specific activity, 150-200 Ci/mumole) was infused into the hepatic artery of 16 patients with inoperable liver metastases over 30-45 min through a permanent intra-arterial catheter. A dynamic sequence during infusion, spot images, whole-body scans and SPECT acquisitions were recorded up to 42 hr. Blood and urine samples were obtained for biodistribution and HPLC analyses. RESULTS: In the 14 patients with adequate tumor perfusion patterns, tumor uptake reached 2%-17.6% ID at the end of infusion. After a washout phase that lasted 18-20 hr, incorporated radioactivity remained steadily associated with the tumor lesions until at least 42 hr after infusion (about 1.4%-11.1% ID). HPLC analysis indicated a virtually 100% first-pass hepatic deiodination of unincorporated [123I]IUdR (about 80%-95% ID recovered in the 42-hr urine). No significant uptake was detected in the bone marrow or in other normal dividing tissues. CONCLUSION: These results encourage further studies to enable dosimetric estimates, optimization of dose regimens, and examination of the therapeutic potential of Auger-electron-emitter-labeled IUdR in cancer therapy utilizing this type of approach.

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In previous studies we demonstrated a high tumor-targeting value of the 123I-labeled thymidine analogue 5-iodo-2'-deoxyuridine (IUdR) infused intra-arterially in patients with liver metastases from colorectal cancer. In the present study we have explored the possibility of enhancing tumor uptake of [123I]IUdR, by biochemical modulation with 5-fluorouracil (5-FU) and 1-folinic acid (FA), a drug combination known to inhibit thymidylate synthetase in tumor cells. The investigation was carried out employing diagnostic imaging doses of [123I]IUdR, much lower than possible therapeutic levels. In the baseline study, [123I]IUdR was infused into the hepatic artery of patients with inoperable liver metastases from colorectal cancer, and a second infusion was performed one week later, after intra-arterial administration of 5-FU and FA. The effect was evaluated by comparing tumor uptake of [123I]IUdR in the second study with that of the baseline study. The average tumor uptake immediately after [123I]IUdR infusion was 9.1% ID in the baseline study, increasing to 14.9% ID after pretreatment with 5-FU and FA. The average enhancement in early tumor uptake of [123I]IUdR induced by biochemical modulation was 72%. This enhancement was sustained at 18 and 42 hours after infusion (stable uptake). The results encourage the pretreatment of patients with 5-FU and FA prior to radioiodinated IUdR administration and suggest its inclusion in therapeutic protocols employing IUdR labeled with 123I or 125I as a source of highly cytotoxic Auger electrons.

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We have previously demonstrated the high tumor targeting potential of the thymidine analogue 125IUdR in experimental animal models following direct intratumoral or locoregional (intracavitary) administration. The aim of the present work was to evaluate the metabolism and selectivity (based on differential cell proliferation kinetics) of 125IUdR incorporation in patients with breast cancer following a similar approach. 125IUdR (4-8 MBq) was injected intratumorally by ultrasound-guided percutaneous injection in 7 patients with breast cancer 24 hours before ablative surgery. Blood and urine samples were collected up to 72 hours after injection and analyzed by HPLC using a C18 reversed-phase column and methanol:water (20:80) as the mobile phase. Following resection, the radioactivity of the tumor and the surrounding tissues was measured in a gamma counter, and microautoradiography was performed on semithin tissue sections to determine the site of tracer incorporation at the cellular level. Activity in plasma peaked at 0.5 to 1 hour after 125IUdR injection (4.96 +/- 1.08% of injected dose/liter), declining thereafter with a mean T1/2 of 11.24 +/- 2.78 hours. By HPLC analysis, undegraded 125IUdR was about 15-30% of total plasma activity, with a biphasic pattern peaking at both 1-3 hours and approximately 12 hours. In addition to free 125I-, about 10% of early plasma activity was constituted by a labeled metabolite (tentatively identified as radio-iodouracil), rising to about 50-60% at later time points. About 70-90% of urinary radioactivity was 125I-, and 5-20% was undegraded 125IUdR in the first 24-hour samples, while the remainder was iodouracil. High tumor/nontumor ratios were obtained (mean 147.4 +/- 125.2, range 27-397) with average tumor/blood ratios at the time of surgery equal to 32.7 +/- 18.6 (range 5-56). An average 0.0244 +/- 0.0189% of the injected dose was present per gram of tumor (range 0.001-0.061% ID/g). Microautoradiography confirmed the high values of tumor/nontumor incorporation ratios and demonstrated the specificity of 125IUdR incorporation mostly in the tumor cell nuclei, with only occasional incorporation by normal-appearing tubular cells. These results suggest the potential of radiolabeled IUdR for tumor targeting in humans, to be used whenever a satisfactory route of locoregional administration allowing for homogeneous tracer distribution within the tumor mass is accessible and in the presence of favorable tumor cell proliferations kinetics.

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The behavior of myocardial blood flow (MBF) regulation in territories supplied by angiographically normal vessels of patients with coronary artery disease (CAD) has been poorly investigated. Resting MBF and coronary reserve were evaluated in 32 patients with stable angina, no previous myocardial infarction, and isolated left anterior descending or left circumflex coronary artery stenosis (> or = 50% diameter narrowing). MBF was measured, in the absence of any medical therapy, by means of dynamic positron emission tomography and 13N-ammonia. MBF measurements at baseline and after intravenous dipyridamole (0.56 mg/kg administered over 4 minutes), were obtained both in the stenosis-related regions and in contralateral territories. As a control group, 14 normal subjects were evaluated according to the same protocol. At rest, the 32 patients with CAD had similar MBF values in the stenotic and remote regions (0.76 +/- 0.21 and 0.77 +/- 0.19 ml/min/g, respectively, p = NS); both these values were significantly (p < 0.01) reduced with respect to mean MBF in normal subjects (1.03 +/- 0.25 ml/min/g). The dipyridamole study was completed in 30 patients; these patients had lower values of maximal MBF in the stenotic than in the remote regions (1.52 +/- 0.65 vs 1.76 +/- 0.68 ml/min/g, p < 0.05); however, both these values were significantly reduced (p < 0.01) with respect to mean dipyridamole MBF in normal subjects (3.66 +/- 0.92 ml/min/g). Thus, in patients with CAD, resting and maximal MBF can be reduced not only in myocardial territories supplied by stenotic arteries, but also in territories supplied by angiographically normal arteries.

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Previous studies have demonstrated the tumor-targeting potential of radioiodinated 5-iodo-2'-deoxyuridine (IUdR) in experimental animal models following direct intratumoral or intracavitary administration. The aim of this study was to measure the tumor uptake and metabolic fate of 5-[125I]iodo-2'-deoxyuridine ([125I]UdR) in humans after a single intratumoral injection. Ten patients with colorectal cancer were injected intratumorally with [125I]UdR) (0.24-3.9 MBq) during endoscopy 24 hr before ablative surgery. Blood and urine samples were collected up to 72 hr after [125I]UdR injection. Following resection, the radioactivity in the tumor and the surrounding tissues was measured in a gamma counter, and microautoradiography was performed on semi-thin tissue sections to assess localization of the radiopharmaceutical at the cellular level. An average of 0.234% of the injected dose was present per gram of tumor (range 0.009-0.918, median value 0.147), and tumor-to-nontumor radioactivity incorporation ratios were high for colonic mucosa when the nontumor tissue was taken at 1 cm (mean 629, range 27-2391) and 15 cm (mean 2387, range 122-12674) from the injection site. Microautoradiography confirmed these high tumor-to-nontumor ratios and demonstrated localization of [125I]UdR in the tumor cell nuclei. These results suggest that radioiodinated IUdR might have potential as a tumor-targeting agent in humans, provided homogeneous intratumoral distribution of the radiopharmaceutical by a suitable route of loco-regional administration can be achieved.

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