ICRP Publication 140: Radiological Protection in Therapy with Radiopharmaceuticals.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer.

BACKGROUND: In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS: We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS: The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION: We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy.

Dopamine and Abeta-induced stress signaling and decrements in Ca2+ buffering in primary neonatal hippocampal cells are antagonized by blueberry extract.

We have shown previously that dietary blueberry (BB) extract supplementation (S) reversed several parameters of neuronal and behavioral (e.g., cognition) aging in rodents. Additionally, findings indicate that COS-7 cells transfected with muscarinic receptor subtypes (e.g., M1) showed decrements in Ca;{2+} clearance following depolarization (Ca;{2+} Recovery time, Ca;{2+}RT) that were antagonized by BB. Since it has been postulated that at least part of the loss of cognitive function in aging may be dependent upon a dysregulation in calcium homeostasis (i.e., Ca;{2+}RT), we assessed whether: a) Ca;{2+}RT would be altered in dopamine (DA)- or amyloid beta (Abeta)-exposed cultured primary hippocampal neuronal cells (HNC), and b) BB pre-treatment of the cells would prevent these deficits. Thus, control or BB (0.5 mg/ml)-treated HNC were exposed to DA (0.1 mM, 2 hrs), Abeta(40) (25 microM, 24 hrs), Abeta(42) (25 microM, 24 hrs), and Abeta(25-35) (25 microM, 24 hrs), and Ca;{2+}RT following KCl-induced depolarization assessed. Ca;{2+}RT was assessed as the % of HNC showing recovery to 50%-70% of control at 5, 10, or 15 min after depolarization. Results indicated that DA significantly lowered Ca;{2+}RT in the HNC at all time points examined after depolarization. However, BB treatment selectively prevented these declines in Ca;{2+}RT. In the case of Abeta, the greatest effects on Ca;{2+}RT were seen when the hippocampal cells were Abeta(42)-treated. These effects were antagonized by BB treatment. Abeta(40) produced fewer deficits on Ca;{2+}RT than those seen when the HNC were pre-treated with either A;{2+}(42) or A;{2+}(25-35), but BB was relatively ineffective in antagonizing the deficits in Ca;{2+}RT produced by A;{2+}(40) or A;{2+}(25-35). Additional analyses indicated that BBs may be exerting their protective effects in the hippocampal cells by altering levels of phosphorylated MAPK, PKCgamma, and phosphorylated CREB. Therefore it appears that at least part of the protective effect of BBs may involve alterations in stress signaling.

Dopamine-induced stress signaling in COS-7 cells transfected with selectively vulnerable muscarinic receptor subtypes is partially mediated via the i3 loop and antagonized by blueberry extract.

Muscarinic receptors (MAChRs) are intimately involved in various aspects of both neuronal and vascular functioning, and there is selective oxidative stress sensitivity (OSS) among MAChR subtypes, with M1, M2, and M4 showing>OSS. OSS was assessed by determining the loss of ability of the cell to extrude or sequester Ca2+ following oxotremorine-induced depolarization following exposure to dopamine (DA) subtypes in transfected COS-7 cells. This OSS can be prevented by pretreatment with blueberry (BB) extract. Present studies were carried out to determine BB treatment of the cells transfected with wild type, truncated or chimeric [where the i3 loop of one receptor was switched with the i3 loop of the other; i.e., M1(M3i3) and M3(M1i3)] receptors would alter DA-induced changes in calcium buffering and would confer protection through alterations in pMAPK, pCREB or PKC signaling. These findings also suggest that BB may antagonize OS effects by lowering activation of pCREB and possibly PKCgamma induced by DA. In the truncated and chimeric receptors, results indicated that BB reduced OSS in response to DA in M1-transfected cells. However, BBs were also effective in preventing these Ca2+ buffering deficits in cells transfected with M1 receptors in which the i3 loop had been removed, but only partially enhanced the protective effects of the M3 i3 loop in the M1(M3i3) chimerics. A similar partial effect of BBs was seen in the M3(M1i3) chimerics which showed increased OSS in response to DA. It appears that antioxidants found in BBs might be targeting additional sites on these chimerics to decrease OSS.

Blueberry extract alters oxidative stress-mediated signaling in COS-7 cells transfected with selectively vulnerable muscarinic receptor subtypes.

Previous research has indicated that selective vulnerability to oxidative stress may be important in determining regional differences in functional declines in neuronal aging. Oxidative stress vulnerability may involve selective deficits in Ca2+ buffering (Ca2+ recovery time following oxotremorine application) to oxidative stress, determined in-part by receptor subtype with M1, M2 and M4 AChR showing greater oxidative stress-induced loss [via dopamine (DA) exposure for 4 hrs] of Ca2+ recovery time than that seen in M3 or M5 cells. Deficits were antagonized by pre-treating M1, M2, or M4 AChR-transfected cells with blueberry (BB) extract. Thus, we assessed whether these differences in oxidative stress vulnerability might involve differential patterns of DA-induced protein kinase (PKCalpha, PKCgamma) and/or cyclic AMP response element binding protein (CREB) activation, and whether these differences might be altered by BB treatment. M1 or M3 AChR-transfected COS-7 cells were exposed to 1 mM DA, and activation of phospho-(p) mitogen-activated protein kinase (MAPK) signaling was examined by immunoblotting analyses. The results showed that DA increased pCREB and pPKCgamma for both M1- and M3-transfected cells, and BBs decreased these DA-induced alterations, when measured by immunoblotting techniques. Taken together these findings suggest that M1/M3 oxidative stress sensitivity differences may involve differential signaling in pMAPK and pCREB under oxidative stress conditions, suggesting that the native protection in these receptors against oxidative stress and inflammation may be derived from reduced activation. These findings also suggest that BB may antagonize oxidative stress effects induced by DA in M1-transfected cells by lowering activation of pCREB, and possibly pPKCgamma.

Assessments for high dose radionuclide therapy treatment planning.

Advances in the biotechnology of cell specific targeting of cancer and the increased number of clinical trials involving treatment of cancer patients with radiolabelled antibodies, peptides and similar delivery vehicles have led to an increase in the number of high dose radionuclide therapy procedures. Optimised radionuclide therapy for cancer treatment is based on the concept of absorbed dose to the dose limiting normal organ or tissue. The limiting normal tissue is often the red marrow, but it may sometimes be the lungs, liver, intestinal tract or kidneys. Appropriate treatment planning requires assessment of radiation dose to several internal organs and tissues, and usually involves biodistribution studies in the patient using a tracer amount of radionuclide bound to the targeting agent and imaged at sequential timepoints using a planar gamma camera. Time-activity curves are developed from the imaging data for the major organ tissues of concern, for the whole body and sometimes for selected tumours. Patient specific factors often require that dose estimates be customised for each patient. In the United States, the Food and Drug Administration regulates the experimental use of investigational new drugs and requires 'reasonable calculation of radiation absorbed dose to the whole body and to critical organs' using the methods prescribed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Review of high dose studies shows that some are conducted with minimal dosimetry, that the marrow dose is difficult to establish and is subject to large uncertainties. Despite the general availability of software, internal dosimetry methods often seem to be inconsistent from one clinical centre to another.

Muscarinic receptor subtype determines vulnerability to amyloid beta toxicity in transfected cos-7 cells.

Research has suggested that there are age-related increases in neuronal sensitivity to insult from oxidative stress (OS) and that the CNS alterations seen in Alzheimer disease (AD) and vascular dementia (VaD) are superimposed upon declining nervous and vascular systems. Since muscarinic receptors (mAChR) may be important in regional sensitivity, regulation of micro- circulation, and in various aspects of both neuronal (AbetaPP processing) and vascular functioning, we postulated that the various mAChR subtypes may show differential sensitivity to OS. Indeed, recent findings indicated that M1, M2, or M4 AChR-transfected COS-7 cells showed greater OS sensitivity [as reflected in Ca2+ buffering (i.e., the ability to extrude or sequester Ca2+ following oxotremorine-induced depolarization)] than those transfected with M3 or M5 AChR when exposed to dopamine. Interestingly, the results from the present study indicate that similar findings were also observed when the cells were exposed to Abeta 25-35 and Abeta 1-40 showed similar effects on M1 and M3 AChR. No effects were seen with Abeta 35-25 or Abeta 40-1. Thus, cells transfected with M1, M2 or M4 AChR showed greater disruptions in calcium regulation (as assessed via fluorescent imaging analysis prior to and following 750 microm oxotremorine) than those transfected with M3 or M5 AChR. We also examined the effects of calcium channel antagonists (e.g., Nifedipine) or antioxidants (vitamin E) in protecting against the deleterious effects of Abeta. Results are discussed in terms of differences in MAChR structure that could lead to selective Abeta effects and the possible implications on memory and AbetaPP processing.

Muscarinic receptor subtype determines vulnerability to oxidative stress in COS-7 cells.

Research has suggested that there may be increased brain-region selective vulnerability to oxidative stress in aging and that Vulnerability to oxidative stress may be important in determining regional differences in neuronal aging. We assessed whether one factor determining vulnerability to oxidative stress might involve qualitative/quantitative differences in receptor subtypes in various neuronal populations. COS-7 cells were transfected with one of five muscarinic receptor subtypes (M1-M5 AChR) to DA (1 mM for 4 h) and intracellular Ca2+ levels were examined via fluorescent imaging analysis prior to and following 750 microM oxotremorine (oxo). Results indicated that the ability of the cells to clear excess Ca2+ (i.e., Ca2+ Recovery) following oxo stimulation varied as a function of transfected mAChR subtype, with DA-treated M1, M2, or M4 cells showing greater decrements in Recovery than those transfected with M3 or M5 AChR. A similar pattern of results in M1- or M3-transfected DA-exposed cells was seen with respect to Viability. Viability of the untransfected cells was unaffected by DA. Pretreatment with Trolox (a Vitamin E analog) or PBN (a nitrone trapping agent) did not alter the DA effects on cell Recovery in the M1-transfected cells, but were effective in preventing the decrements in Viability. The calcium channel antagonists (L and N, respectively), Nifedipine and Conotoxin prevented both the DA-induced deficits in Recovery and Viability. Results are discussed in terms of receptor involvement in the regional differences in Vulnerability to oxidative stress with age, and that loss of neuronal function may not inevitably lead to cell death.

Immunosuppressive effects of (131)I-anti-CD45 antibody in unsensitized and donor antigen-presensitized H2-matched, minor antigen-mismatched murine transplant models.

Iodine-131-labeled anti-CD45 antibody has been added to conventional hematopoietic stem cell transplant preparative regimens to deliver targeted radiation to hematopoietic tissues, with the goal of decreasing relapse rates without increasing toxicity. However, higher radiation doses could be delivered to leukemia cells by antibody if the systemic therapy were decreased or eliminated. To examine the ability of (131)I-anti-CD45 antibody to provide sufficient immunosuppression for transplantation across allogeneic barriers, T-cell-depleted BALB.B marrow was transplanted into H2-compatible B6-Ly5(a) mice after (131)I-30F11 (rat antimurine CD45) antibody with or without varying dose levels of total body irradiation (TBI). Groups of five or six recipient mice per (131)I or TBI dose level per experiment were given tail vein injections of 100 microg of (131)I-labeled 30F11 antibody 4 days before marrow infusion, with or without TBI on day 0. Engraftment, defined as > or =50% donor B cells at 3 months posttransplant, was determined by two-color flow cytometric analysis of peripheral blood granulocytes, T cells, and B cells using antibodies specific for donor and host CD45 allotypes and for CD3. Donor engraftment of > or =80% recipient mice was achieved with either 8 Gy of TBI or 0.75 mCi of (131)I-30F11 antibody, which delivers an estimated 26 Gy to bone marrow. Subsequent experiments determined the dose of TBI alone or TBI plus 0.75 mCi of (131)I-30F11 antibody necessary for engraftment in recipient mice that had been presensitized to donor antigens before transplant, a setting requiring more stringent immunosuppression. Engraftment was seen in > or =80% of presensitized recipients surviving after 14-16 Gy of TBI or 12-14 Gy of TBI and 0.75 mCi of (131)I-30F11 antibody. However, only 28 of 69 (41%) presensitized mice receiving 10-16 Gy of TBI alone survived, presumably because of rejection of donor marrow and ablation of host hematopoiesis. In contrast, 29 of 35 (83%) presensitized mice receiving (131)I-30F11 antibody and 10-14 Gy of TBI survived, presumably because the additional immunosuppression provided by estimated radiation doses of 53 Gy to lymph nodes and 81 Gy to spleen from 0.75 mCi of (131)I-30F11 antibody permitted engraftment of donor marrow. These results suggest that targeted radiation delivered by (131)I-anti-CD45 antibody provides sufficient immunosuppression to replace an appreciable portion of the TBI dose used in matched sibling hematopoietic stem cell transplant.

Effective thresholds for induction of skeletal malignancies by radionuclides.

Our analysis of data from the beagle project completed at the University of Utah has provided some comparisons that appear to be useful in testing the model proposed by Raabe of effective thresholds for induction of skeletal malignancy by bone-seeking radionuclides in beagles. Raabe's model predicted that cumulative skeletal doses of less than about 0.9 to 1.4 Gy from alpha emitters or 28 to 70 Gy from beta emitters deposited in the skeleton require a long enough time for bone cancer expression that the dog's natural lifespan would be exceeded before the tumor appeared. Results from the Utah beagle project seem to confirm these projections for 226Ra, 228Ra and, perhaps, for 90Sr. The lowest doses at which malignant bone tumors were observed in animals injected with these radium isotopes were about 0.9 Gy (226Ra) and 3 Gy (228Ra). For the beta emitter, 90Sr, the lowest doses at which bone tumors were seen were about 18, 50, and 70 Gy with an expectation for naturally occurring tumor of about one. Twenty-six of the two hundred and thirty-three Utah beagles given monomeric 239Pu that developed skeletal malignancies had doses between 0.02 and 0.51 Gy (80 of these dogs had skeletal doses of less than 0.9 Gy). Three dogs of 54 given 241Am with doses lower than 0.9 Gy had bone tumors at 0.23, 0.56, and 0.88 Gy with the expectation of about one naturally occurring case. For 25 animals injected with 228Th at skeletal doses below 0.9 Gy, one bone tumor dog had a dose of about 0.4 Gy, and the expectation of a dog with natural tumor among the group was only about 0.38. Five beagles of 74 given 224Ra with resulting doses of less than 0.9 Gy died with skeletal malignancy at 0.32 Gy or less with an expectation for non 224Ra induced tumor of about one. It appears that Raabe's proposal might be confirmed for some but not all of the radionuclides used in the Utah studies. Models presented in earlier papers by Raabe provide results that are somewhat different from his recent abstract and compare more favorably with those cited herein for Utah dogs. Re-examination of our data for these analyses has suggested a novel concept for calculation of carcinogenic dose to endosteal bone surfaces.

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Oxidative stress protection and vulnerability in aging: putative nutritional implications for intervention.

Research indicates that vulnerability to oxidative stress (OSV) may increase in aging, suggesting that age-related neurodegenerative diseases such as Alzheimer's disease (AD) or vascular dementia (VAD) may be superimposed upon a vulnerable neuronal environment. Determinations in cell models have suggested that the enhanced OSV may be the result of, (a) increases in membrane lipids, especially sphingomyelin and the sphingomyelin metabolite, sphingosine-1-phosphate, (b) decreases in glutathione, and (c) CNS distribution of OS-sensitive neuronal muscarinic receptor subtypes (e.g. M1, M2 and M4). These changes appear to enhance, (a) decrements in cellular calcium buffering following KCl-induced depolarization, and (b) cell death under OS conditions. Among the most effective agents that antagonized cellular OSV were the combination of polyphenolics found in fruits (e.g. blueberry extract) with high antioxidant activity. Subsequent experiments using dietary supplementation with fruit (strawberry) or vegetable (spinach) extracts have shown that such extracts are also effective in forestalling and reversing the deleterious effects of behavioral aging in F344 rats. Thus, it appears that the beneficial effects of the polyphenolics found in fruits and vegetables in neuronal aging and behavior may be similar to those seen with respect to carcinogenesis and cardiovascular disease.

Biomechanical evaluation of occipital fixation.

Many studies have shown a positive correlation among screw pullout strength, screw insertional torque, bone thickness, and areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. Variations are significant in the anatomy of the occipital bone. But no studies have correlated these variables with respect to the two locations commonly used for plate fixation to the occiput. The purpose of this study was to determine the thickness and quality of the occipital bone and to correlate these variables with the insertional torque of screws and the pullout strength of plates secured into two different locations on the occiput. The occiputs of 12 adult human fresh frozen cadaveric specimens were used. The specimens were analyzed by dual-energy X-ray absorptiometry. Direct thickness measurements of the occiput were performed. Areal and volumetric BMD were measured. A simple pelvic reconstruction plate (3.2 mm) was fixed to the occiput either laterally or at the midline with bicortical 4-mm cancellous screws. Torque was recorded at the time of insertion of each screw. Axial pullout tests were performed on all specimens. The peak load, failure load, stiffness, and energy to failure were recorded for each construct. Statistical analysis showed that the average thickness of occipital bone is greater in the midline than laterally. Occipital bone is thicker and screw torque is greater close to the inion. There is a positive correlation between bone thickness, areal BMD as measured by dual-energy X-ray absorptiometry, screw insertional torque, and strength of fixation. A plate fixed in the midline region of the occiput provides more rigid fixation than a plate fixed laterally. Areal BMD correlates better than volumetric BMD with bone thickness and is a reliable predictor of the strength of occipital fixation.

Decorporation: officially a word.

This note is the brief history of a word. Decorporation is a scientific term known to health physicists who have an interest in the removal of internally deposited radionuclides from the body after an accidental or inadvertent intake. Although the word decorporation appears many times in the radiation protection literature, it was only recently accepted by the editors of the Oxford English Dictionary as an entry for their latest edition.

Internal dosimetry for systemic radiation therapy.

The key to effective use of the medical internal radiation dose (MIRD) schema in radioimmunotherapy (RIT) is to understand how it works and what the essential data input requirements are. The fundamental data are acquired from medical imaging. Image interpretation involves (1) collecting data to determine the source-organ activities, (2) plotting the source-organ time-activity curves, (3) integrating the time-activity curves for an estimate of the residence time, and (4) applying the residence time values (for each important source organ) within the MIRD schema to calculate the tissue absorbed dose to target organs and tumors of interest. This article reviews methods for calculating internal dose. It also describes methods for selecting sampling times, integrating the area under the data curves, and customizing a dose assessment for a patient who does not resemble the MIRD phantom. A sample dose assessment is given, together with common mistakes to avoid. Three approaches to red marrow dosimetry are described. With the increased use of RIT agents for cancer treatment, a solid understanding of internal dose methods is essential for treatment planning and follow-up evaluations.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer.

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (90Y-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5 +/- 10.3 mCi/m2) of 90Y-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered approximately 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 90Y. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.

Synthesis and characterization of multiply-tyrosinated, multiply-iodinated somatostatin analogs.

Radio-labeled somatostatin analogs have recently gained popularity as agents useful in intraoperative tumor localization, external scintigraphy and in situ radiotherapy. We have synthesized and characterized a series of novel N-terminally extended multiply-tyrosinated somatostatin analogs that possess high binding affinity for somatostatin receptors, exhibit biological activity comparable to the native peptide and retain these characteristics after iodination. These analogs can be radio-iodinated to high specific activities. Following radioiodination, these analogs exhibit minimal radiolysis and may be clinically useful for tumor localization, scanning and therapy.