astatine and Ovarian-Neoplasms

Radionuclides which decay by the emission of alpha-particles are attractive for certain radioimmunotherapeutic applications. These include the treatment of lymphomas, compartmentally spread malignancies such as ovarian cancer and neoplastic meningitis, and micrometastatic disease. Two alpha-emitting radionuclides of interest for this purpose are 212Bi (60.6 min half life) and 211At (7.2 hr half life). Compared with the beta-emitters commonly used for radiotherapy, the alpha-particles of 212Bi and 211At are of higher energy, much shorter range (less than 100 microm), and considerably higher linear energy transfer. Preliminary results obtained in a variety of in vitro systems and in vivo models have documented the exquisite toxicity of alpha-particles and have established a basis for initiating radiotherapy trials in humans with monoclonal antibodies labeled with alpha-emitting radionuclides.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Bismuth; Female; Half-Life; Humans; Immunoconjugates; Linear Energy Transfer; Lymphoma; Meningitis; Neoplasm Metastasis; Ovarian Neoplasms; Radioimmunotherapy; Radioisotopes

The alpha-emitter (211)At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity.. Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. (211)At was labeled to MX35 F(ab')(2) using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with (211)At-MX35 F(ab')(2) (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. gamma-Camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo.. Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% +/- 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 +/- 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 +/- 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 +/- 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 +/- 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 +/- 1.6 mGy/(MBq/L) (mean +/- SD). No adverse effects were observed either subjectively or in laboratory parameters.. This study indicates that by intraperitoneal administration of (211)At-MX35 F(ab')(2) it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity.

Topics: Adult; Aged; Alpha Particles; Antibodies, Monoclonal; Astatine; Body Burden; Female; Humans; Infusions, Parenteral; Middle Aged; Ovarian Neoplasms; Radioimmunotherapy; Radiometry; Radiopharmaceuticals; Radiotherapy Dosage; Treatment Outcome

The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment.

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Body Weight; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Radiation Dosage; Radioimmunotherapy; Radiometry; Survival Analysis; Time Factors; Tissue Distribution

The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody Affinity; Antibody Specificity; Antigens, Neoplasm; Antineoplastic Agents; Astatine; Carcinoma; Cell Line, Tumor; Female; Gene Expression; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Sodium-Phosphate Cotransporter Proteins, Type IIb; Technetium; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Xenograft Model Antitumor Assays

Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2.. Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution.. The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose.. Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Electrons; Female; Gastric Mucosa; Humans; Immunoconjugates; Immunoglobulin Fab Fragments; Kidney; Lung; Neoplasm Recurrence, Local; Neoplasm, Residual; Ovarian Neoplasms; Peritoneal Neoplasms; Proton Therapy; Radioimmunotherapy; Radiotherapy Dosage; Relative Biological Effectiveness; Risk Assessment; Stomach; Thyroid Gland; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Urinary Bladder

Abstract Purpose: Pretargeted radioimmunotherapy (PRIT) against intraperitoneal (i.p.) ovarian microtumors using avidin-conjugated monoclonal antibody MX35 (avidin-MX35) and (211)At-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PLsuc) was compared with conventional radioimmunotherapy (RIT) using (211)At-labeled MX35 in a nude mouse model.. Mice were inoculated i.p. with 1×10(7) NIH:OVCAR-3 cells. After 3 weeks, they received PRIT (1.0 or 1.5 MBq), RIT (0.9 MBq), or no treatment. Concurrently, 10 additional animals were sacrificed and examined to determine disease progression at the start of therapy. Treated animals were analyzed with regard to presence of tumors and ascites (tumor-free fraction; TFF), 8 weeks after therapy.. Tumor status at baseline was advanced: 70% of sacrificed animals exhibited ascites. The TFFs were 0.35 (PRIT 1.0 MBq), 0.45 (PRIT 1.5 MBq), and 0.45 (RIT). The 1.5-MBq PRIT group exhibited lower incidence of ascites and fewer tumors >1 mm than RIT-treated animals.. PRIT was as effective as RIT with regard to TFF; however, the size distribution of tumors and presence of ascites indicated that 1.5-MBq PRIT was more efficient. Despite advanced disease in many animals at the time of treatment, PRIT demonstrated good potential to treat disseminated ovarian cancer.

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Avidin; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Radioimmunotherapy; Radionuclide Imaging; Tissue Distribution

Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the α-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-µm micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals were sacrificed at several time points, and peritoneal samples were excised and prepared for alpha-camera imaging. Spatial and temporal activity distributions within micrometastases were derived and used for small-scale dosimetry. We observed two activity distribution patterns: uniform distribution and high stable uptake (>100% IA/g at all time points) in micrometastases with no visible stromal compartment, and radial distribution (high activity on the edge and poor uptake in the core) in tumor cell lobules surrounded by fibroblasts. Activity distributions over time were characterized by a peak (140% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 µm. Small-scale dosimetry was performed on a multi-cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity distribution received <25 Gy (EUD=13 Gy), whereas tumors presenting radial activity distribution received mean absorbed doses of <8 Gy (EUD=5 Gy). These results provide new insight into important aspects of TAT, and may explain why micrometastases >100 µm might not be effectively treated by the examined regimen.

Topics: Alpha Particles; Animals; Astatine; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Micrometastasis; Ovarian Neoplasms; Radiometry; Radionuclide Imaging; Radiopharmaceuticals; Radiotherapy Dosage; Treatment Outcome

Avidin-coupled monoclonal antibody MX35 (avidin-MX35) and astatine-211-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) were administered in mice to assess potential efficacy as an intraperitoneal (i.p.) therapy for microscopic tumors. We aimed to establish a timeline for pretargeted radioimmunotherapy using these substances, and estimate the maximum tolerable activity.. (125)I-avidin-MX35 and (211)At-B-PL(suc) were administered i.p. in nude mice. Tissue distributions were studied at various time points and mean absorbed doses were estimated from organ uptake of (211)At-B-PL(suc). Studies of myelotoxicity were performed after administration of different activities of (211)At-B-PL(suc).. We observed low blood content of both (125)I-avidin-MX35 and (211)At-B-PL(suc), indicating fast clearance. After sodium perchlorate blocking, the highest (211)At uptake was found in kidneys. Red bone marrow (RBM) accumulated some (211)At activity. Mean absorbed doses of special interest were 2.3 Gy/MBq for kidneys, 0.4 Gy/MBq for blood, and 0.9 Gy/MBq for RBM. An absorbed dose of 0.9 Gy to the RBM was found to be safe. These values suggested that RBM would be the key dose-limiting organ in the proposed pretargeting scheme, and that blood data alone was not sufficient for predicting its absorbed dose.. To attain a favorable distribution of activity and avoid major toxicities, at least 1.0 MBq of (211)At-B-PL(suc) can be administered 24 hours after an i.p. injection of avidin-MX35. These results provide a basis for future i.p. therapy studies in mice of microscopic ovarian cancer.

Topics: Animals; Antibodies, Monoclonal; Astatine; Avidin; Biotinylation; Bone Marrow; Female; Iodine Isotopes; Isotope Labeling; Kidney; Lysine; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Polymers; Radioimmunotherapy; Tissue Distribution

Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, (211)At, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2 MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of (51)Cr-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor- and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following alpha-RIT with (211)At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10 Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic alpha-RIT when using (211)At-MX35-F(ab')(2).

Topics: Animals; Antibodies, Monoclonal; Astatine; Female; Glomerular Filtration Rate; Humans; Kidney; Mice; Mice, Nude; Organometallic Compounds; Ovarian Neoplasms; Radioimmunodetection; Transplantation, Heterologous

Topics: Alpha Particles; Animals; Antineoplastic Agents; Astatine; Bismuth; Brain Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Ovarian Neoplasms; Radioimmunotherapy; Radioisotopes

The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the alpha-emitter 211At, since their biokinetic properties match the short physical half-live of 211At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumor-bearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125I, the 211At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.

Topics: Animals; Astatine; Benzoates; Cell Line, Tumor; Female; Humans; Maleimides; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Radiometry; Radiopharmaceuticals; Receptor, ErbB-2; Succinimides; Tissue Distribution; Transplantation, Heterologous

To investigate the potential use of astatine-211 (211At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma.. Four-week-old nude mice were inoculated intraperitoneally with 5 . 10(6) SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and 211At-labeled antibody was evaluated.. Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between 211At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq 211At-trastuzumab, and different groups received 5, 50, or 500 microg trastuzumab on Day 7. The increase from 5 to 50 microg trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 microg trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq 211At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls.. The combination of 500 microg trastuzumab and 400 kBq 211At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Astatine; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Radiation Tolerance; Radioimmunotherapy; Radiotherapy Dosage; Receptor, ErbB-2; Trastuzumab

To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2.. Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF).. When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy.. As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.

Topics: Animals; Antibodies, Monoclonal; Astatine; Data Interpretation, Statistical; Dose Fractionation, Radiation; Female; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Radiation Dosage; Radioimmunotherapy; Radiopharmaceuticals; Treatment Outcome

The use of alpha-particle emitters in radioimmunotherapy (RIT) appears to be promising. We previously obtained convincing results in the treatment of microscopic intraperitoneal ovarian cancer in nude mice by using the alpha-emitter 211At. This study was performed to evaluate the relative biological effectiveness (RBE) of 211At compared with that of 60Co gamma-irradiation in an RIT model. Our endpoint was growth inhibition (GI) of subcutaneous xenografts.. GI after irradiation was studied with subcutaneous xenografts of the human ovarian cancer cell line NIH:OVCAR-3 implanted in nude mice. The animals received an intravenous injection of 211At-labeled monoclonal antibody MX35 F(ab')2 at different levels of radioactivity (0.33, 0.65, and 0.90 MBq). Control mice received unlabeled MX35 F(ab')2 only. To calculate the mean absorbed dose to tumor, a separate biodistribution study established the uptake of 211At in tumors and organs at different times after injection. External irradiation of the tumors was performed with 60Co. Tumor growth was monitored, and the normalized tumor volume (NTV) was calculated for each tumor. GI was defined by dividing the NTV values by the fitted NTV curve obtained from the corresponding control mice. To compare the biologic effects of the 2 radiation qualities, the mean value for GI (from day 8 to day 23) was plotted for each tumor as a function of its corresponding absorbed dose. From exponential fits of these curves, the doses required for a GI of 0.37 (D37) were derived, and the RBE of 211At was calculated.. The biodistribution study showed the uptake of the immunoconjugate by the tumor (amount of injected radioactivity per gram) to be 14% after 7 h. At 40 h, the ratio of uptake in tumors to uptake in blood reached a maximum value of 6.2. The administered activities of 211At corresponded to doses absorbed by tumors of 1.35, 2.65, and 3.70 Gy. The value (mean+/-SEM) for D37 was 1.59+/-0.08 Gy. Tumor growth after 60Co external irradiation showed a value for D37 of 7.65+/-1.0 Gy. The corresponding RBE of 211At irradiation was 4.8+/-0.7.. Using a tumor GI model in nude mice, we were able to derive an RBE of alpha-particle RIT with 211At. The RBE was found to be 4.8+/-0.7.

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Cell Line, Tumor; Cobalt Radioisotopes; Dose-Response Relationship, Radiation; Female; Humans; Isotopes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Radioimmunotherapy; Radioisotopes; Radiometry; Relative Biological Effectiveness; Time Factors

The aim of the study was to establish and refine a preclinical model to alpha-immunoradiotherapy of ovarian cancer.. At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival.. A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the alpha-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect.. Use of the short-range, high-linear energy transfer alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.

Topics: Animals; Antibodies, Monoclonal; Astatine; Benzoates; Cell Division; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Dose-Response Relationship, Radiation; Female; Humans; Isotopes; Mice; Mice, Inbred BALB C; Mice, Nude; Monte Carlo Method; Neoplasm Transplantation; Ovarian Neoplasms; Radioimmunotherapy; Radiometry; Time Factors; Tissue Distribution; Trimethyltin Compounds

The purpose of the present study was to investigate the therapeutic efficacy of 211At-labelled specific monoclonal antibody MOv18 in nude mice with intraperitoneal growth of the human ovarian cancer cell line OVCAR3. In the first part of the study the antibody was injected intraperitoneally when the cancer growth was microscopic. The injected activity was 485-555 kBq. The median survival for treated mice was 213 days compared to 138 days for untreated mice (p < 0.014, log-rank test). No obvious toxicity was seen. Thirty-three percent of the mice were apparently free of cancer after 7 months and were probably cured. In the second part of the study mice with macroscopic cancer and signs of ascites were injected intraperitoneally with the same 211At-labelled antibody (377-389 kBq). This treatment possibly delayed the production of ascites. Hopefully radioimmunotherapy with regionally administered 211At-labelled antibody will be of value in women with ovarian cancer as well.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Ascites; Astatine; Female; Humans; Immunoconjugates; Mice; Mice, Nude; Ovarian Neoplasms; Palliative Care; Peritoneal Neoplasms; Radioisotopes; Transplantation, Heterologous; Tumor Cells, Cultured

We compared the therapeutic efficacy of alpha and beta emitting radiocolloids for the treatment of experimental malignant ascites. 211At is an almost pure alpha-emitter. As 211At-tellurium colloid, the dose survival curve is linear and extrapolates through the origin in a manner similar to other high linear energy transfer radiations. Doses of 25 microCi were curative. Less than curative doses showed a graded prolongation of median survival. In cured mice, long term histological changes were seen in thyroid tissue. Acute changes were seen in the gastrointestinal tract as early as 2 hr after radiocolloid administration; these changes reached a plateau at 6 hr and were essentially gone 36 hr later. By comparison, radiocolloids of the beta emitters 32P, 165Dy and 90Y were not curative, but relatively large doses did substantially prolong median survival. The doses for maximal effect were 150 microCi 32P-chromic phosphate, 8000 microCi ++165Dy-ferric hydroxide macroaggregates and 200 microCi 90Y-citrate. The most compelling reason for the increased therapeutic efficacy of 211At-tellurium colloid is the direct and densely ionizing character of the emitted alpha radiations.

Topics: Alpha Particles; Animals; Ascites; Astatine; Colloids; Dysprosium; Electrons; Female; Half-Life; Intestinal Mucosa; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Ovarian Neoplasms; Particle Size; Phosphorus Radioisotopes; Radioisotopes; Thyroid Gland; Yttrium Radioisotopes

An investigation of the efficacy of astatine-211--tellurium colloid for the treatment of experimental malignant ascites in mice reveals that this alpha-emitting radiocolloid can be curative without causing undue toxicity to normal tissue. By comparison, negatron-emitting phosphorus-32 as colloidal chromic phosphate had no antineoplastic activity. The most compelling explanation for this striking difference is the dense ionization and short range of action associated with alpha-emission. These results have important implications for the development and use of alpha-emitters as radiocolloid therapy for the treatment of human tumors.

Topics: Alpha Particles; Animals; Ascites; Astatine; Cell Survival; Chromium; Chromium Compounds; Colloids; Female; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Phosphates; Phosphorus Radioisotopes; Radioisotopes; Tellurium; Transplantation, Homologous