Tumor uptake and mitotic activity pattern of 5-[I-125]iodo-2'-deoxyuridine after intravesical infusion in patients with bladder cancer

In patients with bladder cancer, little is known about diffusion in the tumor mass of 5-iodo-2'-deoxyuridine (IUdR) administered intraluminally, although previous studies based on external scanning have shown promising tumor-targeting properties of IUdR instilled intravesically, This study compared the pattern of IUdR uptake by bladder cancer cells with the actual distribution of mitotic activity, as evaluated by incubation of ex vivo tumor specimens with tritiated thymidine, Methods: The [I-125]IUdR (2-13 MBq) was instilled over 1-3 hr in the bladder of four patients with bladder cancer scheduled for ablative surgery. Twenty-four hours later, surgical samples were assayed for radioactivity and processed for microautoradiography, while fresh tumor specimens were fragmented, incubated with [H-3]thymidine and further processed for microautoradiography. The diffusion of labeled IUdR across the bladder wall was evaluated by blood sampling, Results: Tumor incorporation of [(125)]]IUdR 24 hr after intravesical instillation was 0.002%-0.05% ID/g, while the average tumor-to-normal bladder ratio was about 20, Microautoradiography showed that [I-125]IUdR incorporation was confined to tumor cells in the most superficial layers of the bladder, while incubation of the tumor fragments with [H-3]thymidine demonstrated the presence of diffuse mitotic activity also in the deeper tumor mass. Diffusion of labeled IUdR in the general circulation was minimal. Conclusion: Poor diffusion in the tumor mass makes *IUdR unsuitable for intracavitary therapy of bladder cancer, but the role of such an approach in the postsurgical ''sterilization'' of cancer remnants floating in the bladder lumen after partial cystectomy should be explored

Tumor targeting potential and metabolism of 5-(125-I)-Iodo-2’-Deoxyuridine injected intratumorally in patients with breast cancer.

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

Tumor targeting in vivo and metabolic fate of 5-(Iodine-125)-Iodo-2’- Deoxyuridine following intratumoral injection in patients with colorectal cancer.

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

Tumor targeting by intra-arterial infusion of 5-[123I]iodo-2'-deoxyuridine in patients with liver metastases from colorectal cancer

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/μmole) 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