[131I]IAZA as a molecular radiotherapeutic (MRT) drug: wash-out with cold IAZA accelerates clearance in a murine tumor model.

Based on animal model studies, [131I]IAZA may be useful as an adjunct radiotherapeutic (MRT) drug for the treatment of tumor hypoxia. However, radioactivity in the blood of patients and healthy volunteers dosed with [123I]IAZA has a protracted terminal elimination phase in which clearance is influenced by free [123I]IAZA and possibly by unidentified metabolites. The current work reports that about 40% of the radioactivity in human serum is associated with the serum protein fraction, and that the free:bound ratio is constant at about 60:40 for at least the first 135 min after injection, as determined by radio-HPLC analyses. In order to modulate the clearance of bound and free radioactive IAZA, nonradioactive (cold) IAZA was administered i.v. 1 h following injection of high specific activity [125I][IAZA in the Balb/C EMT-6 murine tumor model. This 'wash out' procedure reduced the concentrations of radioactivity by at least 40% in all tissues, with greatest effect in kidney and liver, and least in tumor. As a result, the tumor:blood ratio increased from 5.8 to 8.5 at 4 h post-injection. This effect would be advantageous for the use of [131I]IAZA as an MRT drug. Optimization of intervals between radioactive and wash out dose, and confirmation of the self-irradiation dose to all tissues, remain to be undertaken before [131I]IAZA can be tested as a low-dose-rate MRT supplement to external beam x-ray radiotherapy.

Radioactivity of blood samples taken from thyroidectomized thyroid carcinoma patients after therapy with (131)I.

BACKGROUND: Occasionally, blood samples may be required from thyroid cancer patients after they have been given the therapy dose of (131)I, as part of necessary medical management of comorbidities. Thus, in the days after (131)I administration, medical health professionals may be involved in the withdrawal, handling, and manipulation of radioactive blood samples. The purpose of this study was to quantify the amount of radioactivity in blood samples taken from thyroidectomized thyroid carcinoma patients after the administration of therapeutic activities of (131)I. METHODS: For dosimetry purposes, serial blood sampling is performed on thyroidectomized thyroid carcinoma patients prior to therapy with (131)I. The quantities of radioactive material present in these blood samples were expressed as a percentage of the administered activity and then extrapolated to the high levels of (131)I used in therapy for 377 patients in this study. The corresponding radiation exposure rate from the blood samples was then calculated to determine what radiation protection methods were required for staff handling these samples. RESULTS: The average amount of radioactivity in a 1 mL blood sample at 1 hour postadministration of 5.5 GBq (150 mCi) of (131)I was 0.2 ± 0.15 MBq (5.4 ± 4.0 µCi). This corresponds to an exposure rate of 1.23 µSv/h (0.123 mrem/h) at 10 cm from the sample. For samples obtained beyond 24 hours after a therapeutic administration of 5.55 GBq (150 mCi), the exposure levels are approximately equal to background radiation. CONCLUSION: The data in this study indicate that the radiation exposure from blood samples withdrawn from thyroidectomized thyroid cancer patients is low. However, to ensure that staff members are exposed to minimal levels of radiation, it is imperative that staff members who are involved in withdrawing, handling, or manipulating radioactive blood samples adhere to the recommended radiation safety practices.

Data on repeated (131)I-WB scans and the incidence of positive Tg and negative (131)I-WBS in DTC patients from a 24 months study.

We present data on repeated iodine-131 whole body scans ((131)I-WBS) in differentiated thyroid cancer patients (DTC) after surgery and (131)I remnant ablation and on increased thyroglobulin (Tg) with negative (131)I-WBS, in a retrospective study at our hospital. A total of 106 patients (91 female and 15 male) treated with (131)I for DTC met the inclusion criteria. The mean age of the patients was 45 years, age range 16-81 years. A total of 101 patients had complete 24 months follow-up following (131)I remnant ablation treatment. The mean (131)I dose administered after the first 6 months of follow- up was 3GBq while mean total dose was 4.9GBq, range 1.1-7.4GBq. Our results showed that at the end of the first 6 months post treatment, 58/101 patients had a negative (131)I-WBS. By the end of the 4th (131)I treatment at 24th months, the remaining 43 patients became negative for (131)I-WBS. We found increased Tg and negative (131)I-WBS in 2 of the 101 patients at the 24th months examination the so called Tg elevated negative (131)I-WBS (TENIS syndrome). The possible explanation of this syndrome is discussed. In conclusion, our study in DTC operated patients does not support the use of repeated diagnostic (131)I-WBS after an undetectable Tg because we found no Tg rebound in patients with negative (131)I-WBS, after 24 months of follow-up with serial measurements of Tg on and of suppression with L thyroxine.

Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma.

UNLABELLED: One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve. METHODS: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol. RESULTS: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect. CONCLUSION: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.

Evaluation of DNA aptamers directed to thrombin as potential thrombus imaging agents.

Two DNA aptamers directed against two separate exosites on human alpha-thrombin were evaluated for thrombus-imaging potential. Aptamer ODN 1 is directed to the thrombin substrate binding site (exosite 1). Our finding that ODN 1 competes with fibrin for binding to exosite 1 on thrombin suggests that ODN 1 will not be useful for thrombus imaging. Aptamer ODN 2 is directed against the thrombin heparin binding site (exosite 2). ODN 2 bound to model thrombi that were formed either by clotting purified fibrinogen with thrombin, or by recalcifying citrated plasma. As the thrombin content of thrombi was increased the rate of ODN 2 uptake into preformed thrombi increased, whereas the rate of release of ODN 2 out of preformed thrombi decreased. This in vitro data suggested that ODN 2 might be useful for thrombus imaging because it can bind to exosite 2 on fibrin-bound thrombin. However, in a rabbit jugular vein model using thrombus supplemented with human thrombin, ODN 2 uptake was equal to the ovalbumin control, and did not reflect thrombin content. While the in vitro results with ODN 2 were consistent with thrombus imaging, the rapid clearance of ODN 2 from circulation, combined with slow mass transfer in the clot, seem to work against in vivo thrombin-dependent imaging or washout analysis.

Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers.

BACKGROUND AND OBJECTIVE: Little is known about the pharmacokinetics of allergens for local immunotherapy. Thus, we studied the pharmacokinetics in allergic volunteers of a commercial allergenic vaccine in orosoluble tablets (LAIS(R), Lofarma S.p.A). METHODS: The carbamylated monomeric allergoid derived from Parietaria judaica major allergen (Par j 1), characterized by maintenance of the original molecular size, and the native allergen, were radiolabelled with 123I, then incorporated into the commercial soluble tablets and administered to allergic subjects. Early sequential and late static scintigraphic acquisitions were performed, and plasma radioactivity was measured at different time intervals. RESULTS: No difference in local pharmacokinetics was observed between the allergen and the allergoid: part of the tracer was retained in the mouth for at least 2 h after swallowing. No direct absorption through the oral mucosa could be detected, as plasma radioactivity increased only after swallowing and peaked at 2 h. However, the plasma peak attained with the allergoid in tablets was significantly higher with respect to the native allergen. Finally, some undegraded allergoid, but not the allergen, could be constantly detected in the bloodstream at plasma peak. CONCLUSIONS: The results showed a similar behaviour of the allergoid and the allergen in tablets as far as their local kinetics are concerned, whereas plasma peak was higher with the allergoid than with the allergen. Therefore we conclude that the chemical modification of the allergen may affect its pharmacokinetics, by making it less susceptible to enzymatic degradation.

In vivo modulators of antibody kinetics.

The aim of the present study was to summarize the effect of in vivo modulation of antibody kinetics and to present new data on the in vivo effect of the cell membrane active detergent Tween 80 and the cytokine interleukin-2 (IL-2) on the accumulation and clearance of a radioactive antibody. Mice bearing Lewis lung carcinoma xenografts and rats bearing DMBA-induced mammary carcinomas were studied after injecting I-125 labeled IgG1 monoclonal antibody (3c4c7g6) raised against a tyrosine kinase receptor protein Tie. Expression of Tie is known to be abundant in vascular endothelia and possibly related to malignant angiogenesis. Tween 80 was administered intratumorally (0.04% of tumor volume), whereas IL-2 was administered intraperitoneally. In the Lewis lung tumor model, the absolute tumor uptake varied between 2 and 5% ID/g, and maximum uptake was achieved after 24 h with Tween, and after 48 h without Tween. Tween manipulation did not increase the uptake in any normal organ, but it enhanced antibody clearance from the blood. In the DMBA rat model, IL-2 had no effect on blood clearance, but enhanced the uptake of Tie antibody into the tumor from 2.5-0.9 to 4.5-0.4% ID/g at 48 h. These data indicate that antibody biodistribution and pharmacokinetics can be modulated by a surface detergent and a cytokine, giving decreased exposure to critical organs, and increased uptake into the tumor. This type of manipulation provides an opportunity to optimize radioimmunotherapy.

Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody.

The ability to deliver radiation selectively to lymphohematopoietic tissues may have utility in conditions treated by myeloablative regimens followed by bone marrow transplantation. Since the CD45 antigen is the most broadly expressed of hematopoietic antigens, we examined the biodistribution of radiolabeled anti-CD45 monoclonal antibodies in normal mice. Trace 125I or 131I-labeled monoclonal antibodies 30G12 (rat IgG2a), 30F11 (rat IgG2b), and F(ab')2 fragments of 30F11 were injected i.v. at doses of 5 to 1000 micrograms. For both intact antibodies, a higher percentage of injected dose/g (% ID/g tissue) in blood was achieved with higher antibody doses. However, as the dose of antibody was increased, the % ID/g in the target organs of spleen, marrow, and lymph nodes decreased. At doses between 5 and 10-micrograms, % ID/g in these tissues exceeded that in lung, the normal organ with the highest concentration of radiolabel. In contrast, thymus was the only hematopoietic organ in which the % ID/g increased with increasing antibody dose, although at high dose the % ID/g was still far below that achieved in the other hematopoietic organs. Antibody 30F11 F(ab')2 fragments were cleared more quickly than intact antibody from blood and from both target and nontarget organs, although the relationship between increasing antibody dose and decreasing % ID/g in spleen, marrow, and lymph nodes was observed. The time-activity curves for each dose of antibody were used to calculate estimates of radiation absorbed dose to each organ. At the 10-micrograms dose of 30G12, the spleen was estimated to receive a radiation dose that was 13 times more than lung, the lymph nodes 3 to 4 times more, and the bone marrow 3 times more than lung. For each antibody fragment dose, the radiation absorbed dose per MBq 131I administered was lower because the residence times of the fragments were shorter than those of the intact antibody. Thus these estimates suggested that the best "therapeutic ratio" of radiation delivered to target organ as compared to lung was achieved with lower doses of intact antibody. We have demonstrated that radiolabeled anti-CD45 monoclonal antibodies can deliver radiation to lymphohematopoietic tissues with relative selectivity and that the relative uptake and retention in different hematolymphoid tissues change with increasing antibody dose.

Use of second antibody in radioimmunotherapy.

In this study, a second antibody was directed against the first antitumor antibody to accelerate clearance of the 131I-labeled first antibody and improve tumor to normal tissue ratios of radioactivity. The value of this method in improving the therapeutic index of radioimmunotherapy with 131I-antibody to CEA has been investigated in nude mice bearing xenografts of human colon carcinoma and in 5 patients with colorectal cancer. The xenografts did not become saturated with anti-CEA as the administered dose was increased to therapeutic levels. At these high dose levels, the second antibody increased tumor to blood ratios to a maximum of 155:1, 48 times the level in controls that did not receive the second antibody. In 5 patients given 50 mCi of anti-CEA, there was no significant toxicity with the second antibody; clearance of radioactivity was accelerated; and tumor imaging was enhanced. The second antibody appears to have the potential to improve the therapeutic index of radioimmunotherapy.

Effects of alpha-adrenoceptor agonists and antagonists on thyroid hormone secretion.

The effects of various alpha-adrenoceptor agonists and antagonists on blood radioiodine levels were studied in mice pre-treated with 125I and thyroxine. The non-selective alpha-adrenoceptor agonist noradrenaline and the selective alpha 1-adrenoceptor agonist phenylephrine both enhanced blood radioiodine levels. Noradrenaline was more potent than phenylephrine. Contrary, the selective alpha 2-adrenoceptor agonist clonidine depressed basal levels of blood radioiodine. The non-selective alpha-adrenoceptor antagonist phentolamine and the selective alpha 1-adrenoceptor antagonist prazosin both inhibited the noradrenaline-induced elevation of radioiodine levels, whereas the alpha 2-adrenoceptor antagonist yohimbine had no such effect, except at a high dose level. All three alpha-adrenoceptor agonists, noradrenaline, phenylephrine and clonidine, inhibited the radioiodine response to TSH. In addition, TSH-induced increase in radioiodine levels was inhibited by prazosin, whereas yohimbine had no effect. Phentolamine inhibited the radioiodine response to TSH when given 2 h prior to TSH, whereas when given 15 min prior to TSH the response to TSH was potentiated by phentolamine. It is concluded, that under in vivo conditions in the mouse, alpha 1-adrenoceptor activation stimulates basal thyroid hormone secretion and inhibits TSH-induced thyroid hormone secretion. Further, alpha 2-adrenoceptor activation inhibits basal thyroid hormone secretion. In addition, TSH-induced thyroid hormone secretion is inhibited by alpha 1-adrenoceptor antagonism. Thus, alpha-adrenoceptors induce both stimulatory and inhibitory effects of thyroid function.

Blood leakage and melphalan leakage from the perfusion circuit during regional hyperthermic perfusion for malignant melanoma.

In regional hyperthermic perfusion with melphalan for patients with malignant melanoma of the leg, plasma leakage between the perfusion circuit and the systemic circulation was 4-7 ml X min-1. The melphalan concentration in the perfusate was biphasic, with half-lives of 8-12 mins for the initial phase and 19-28 mins for the second phase, after the first dose. After a second dose, the corresponding values were 11-13 and 26-34 mins. The highest concentration in general circulation was 0.38 micrograms X ml-1.