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PubMed1995

Comparative assessment of single-dose and fractionated boron neutron capture therapy.

The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

DNA fingerprinting analysis of radiation-induced rat skin tumors.

DNA fingerprinting analysis was performed on rat skin tumors induced by high linear energy transfer neon ion radiation. Most of these tumors (13/15) showed DNA-fingerprint variability between independently isolated tumors from the same animal. These changes include multiple band shifts and extra bands. Comparisons of DNA fingerprints were also made on successive biopsy samples from the same tumor. Each of 3 neon-induced tumors and 2 of 8 electron (low LET) induced tumors showed progressive loss of amplified sequences, gain of amplified sequences, deletions, band shifts, and the appearance of extra bands in progressive biopsies. These results provide evidence for LET-specific effects on genomic instability in radiation-induced rat skin tumors.

Animals↗

PubMed1995

p53 alterations in plutonium-induced F344 rat lung tumors.

The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.

Adenocarcinoma↗

PubMed1994

Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells.

Radioiodinated m-iodobenzylguanidine (MIBG) has been used with only limited success for the treatment of neural crest tumors including neuroblastoma. Use of an MIBG analogue labeled with 211At could be advantageous because of the shorter range and higher linear energy transfer of its alpha-particle emissions compared with the beta-particles emitted by 131I. The potential utility of m-[211At]astatobenzylguanidine for the treatment of neuroblastoma was investigated in vitro using 3 human neuroblastoma cell lines known to take up MIBG [SK-N-SH, SK-N-BE(2C), and SK-SY5Y] and a control line lacking MIBG uptake (SK-N-MC). Maximum binding of m-[211At]astatobenzylguanidine ([211At] MABG) to 5 x 10(5) cells after a 2-h incubation ranged from 61% for SK-N-SH to 1% for SK-N-MC. Using a limiting dilution clonogenic assay, the cytotoxicity for SK-N-SH cells of [211At]MABG was compared with [211At]astatide and no-carrier-added [131I]MIBG. A D0 of 5.8 nCi/ml was calculated for [211At]MABG compared with 482 nCi/ml for [211At] astatide, indicating a more than 80-fold enhanced cytotoxicity for the specifically targeted alpha-particles of [211At]MABG. For [211At]MABG, the D0 corresponded to only 6.4 211At atoms bound/cell compared with 9000 atoms/cell for no-carrier-added [131I]MIBG. The D0 values measured for [211At]MABG treatment of SK-SY5Y, SK-N-BE(2C), and SK-N-MC cells were 50, 5.8, and 11,043 nCi/ml, respectively, corresponding to 7.04, 6.46, and 171.79 211At atoms bound/cell. In conclusion, these results have demonstrated that [211At]MABG is considerably more cytotoxic than [131I]MIBG and that [211At]MABG could have great potential as a radiotherapeutic agent for the treatment of neuroblastoma.

Antineoplastic Agents↗

PubMed1994

Radiotoxicity of platinum-195m-labeled trans-platinum (II) in mammalian cells.

The chemotoxicity and radiotoxicity of trans-dichlorodiammineplatinum (II) labeled with 195mPt (trans-195mPt) are investigated to ascertain the potential of radioplatinum coordination complexes as antineoplastic agents. Platinum-195m, with a half-life of about 4 days, is a prolific emitter of low-energy Auger electrons because of the high probability of internal conversion in its isomeric transitions. The kinetics of cellular uptake and retention after incubation and the radiotoxicity of this Auger electron emitter in the form of trans-195mPt is investigated using cells of the Chinese hamster V79 cell line. The cellular uptake of 195mPt reaches a plateau in about 3 to 5 h of incubation and varies nonlinearly with the extracellular concentration of radioactivity. The radioactivity is eliminated from the cells after incubation with an effective half-life of 24 h. Cell survival data, when corrected for the chemical toxicity of nonradiolabeled trans-platinum, give a cell survival curve typical for radiations with high linear energy transfer. At 37% survival, the mean lethal cellular uptake is about 1.0 mBq/cell. Dosimetric considerations, based on subcellular distribution of the radionuclide, yield a value of 4.8 for the relative biological effectiveness when compared with 250 kVp X rays. Theoretical Monte Carlo track-structure calculations indicate that the density of radical species produced in liquid water in the immediate vicinity of a 195mPt decay site is substantially greater than the density of species along the track of a 5.3 MeV alpha particle. This explains qualitatively the efficacy of 195mPt in causing high-LET radiation type biological effects. The extreme radiotoxicity of intranuclearly localized 195mPt, in conjunction with the proclivity of platinum chemotherapy agents to bind to DNA in the cell nucleus, suggests that the combination of chemical effects and the effects of Auger electrons that can be obtained with radioplatinum coordination complexes may have potential in the treatment of cancer.

Animals↗

PubMed1994

[Experimental study of different histologic types of pulmonary cancers induced by irradiation].

Recent epidemiologic studies suggested that some histologic types of carcinomas were preferentially induced in the lung by irradiation, whatever the mode of exposure and the radiation quality. Since smoking and other environmental airborne pollutants may be strong confounding factors in humans, we have investigated whether histological subtypes were dependent or not on the mode of exposure, in a large series of 9000 rats exposed to external and internal sources at high and low Linear Energy Transfer. Despite comparable overall risk coefficients in rats and humans, our results show that histological types are influenced not only by dose but also by radiation quality and heterogeneity of dose delivering. We suggest that extrapolation from one group to an other take this information in consideration.

Animals↗

PubMed1994

Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate.

Because of their short range and high linear energy transfer, alpha-particles may be particularly effective in the treatment of neoplastic meningitis. Monoclonal antibody 81C6 was labeled with alpha-particle-emitting 211At using N-succinimidyl3-[211At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 x 10(5) TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4-18 microCi of 211At-labeled specific 81C6 antibody or isotype-matched control 211At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 microCi 211At-labeled 81C6 produced statistically significant (P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-microCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 microCi of 211At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 microCi of 211At-labeled 81C6 increased median survival by 113% (P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 microCi of 211At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 x 10(6) TE-671 cells and given a single dose of 18 microCi of 211At-labeled 81C6 or 211At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline (P < 0.001) and control antibody (P < 0.05). These results suggest that treatment with 211At-labeled monoclonal antibodies may be a valuable approach for neoplastic meningitis.

Alpha Particles↗

PubMed1993

Accelerated heavy particles and the lens. VII: The cataractogenic potential of 450 MeV/amu iron ions.

PURPOSE: To determine the cataractogenic potential dose of high velocity iron ions as a fixation of dose administered singly or fractionated. The dose is critical to risk assessment and to theories of radiation action and cataractogenesis. METHODS: Twenty-eight-day-old rats were examined by slit-lamp biomicroscopy on a weekly-bi-weekly basis for more than 2 yr after radiation exposure. For the acute exposure study doses of 1, 2, 5, 25, and 50 cGy were evaluated. The fractionated regimens involved total doses of 2, 25, and 50 cGy. The reference radiation consisted of 50, 100, 200, or 700 cGy of 250 kilovolt (peak) x-rays. RESULTS: In accordance with previous findings in the rat using 570 MeV/amu 40Ar ions, the relative biologic effectiveness increased rapidly with decreasing dose, reaching values as high as 100. Unlike 40Ar ions, fractionation of the 56Fe doses did not produce a consistent enhancement at any of the doses examined. CONCLUSIONS: The data support the previous findings of a high cataractogenic potential for high linear energy transfer (LET) radiation. The effectiveness for the production of cataracts increases with decreasing dose relative to x-rays and is independent of dose protraction. Although the present study did not reveal a consistent enhancement of effect when the ions were applied in fractions, the results are consistent with at least one theory of the inverse dose-rate effect observed for high-LET radiation.

Animals↗

PubMed1996

p53, erbB-2 and K-ras gene alterations are rare in spontaneous and plutonium-239-induced canine lung neoplasia.

Inhalation of high-linear energy transfer radiation in the form of radon progeny is a suspected cause of human lung cancer. To gain insight into the types of genetic derangement(s) caused by this type of radiation, lung tumors from beagle dogs exposed to 239PuO2 and those arising in animals with no known carcinogen exposure were examined for evidence of aberrations in genes known to be altered in lung tumors. Altered expression of the p53 tumor suppressor gene and proto-oncogene erbB-2 proteins (p185erbB2) was evaluated by immunohistochemical analysis of 117 tumors representing different histological types in exposed (n = 80) and unexposed (n = 37) animals. Twenty-eight tumors were analyzed for K-ras proto-oncogene mutations by polymerase chain reaction amplification and direct sequencing. Fourteen percent (16/116) of all lung neoplasms showed elevated nuclear accumulation of p53 protein. Regardless of exposure history, adenosquamous and squamous cell cancers comprised 94% of all tumors with p53 abnormalities. Eighteen percent (21/117) of all tumors had evidence in codons 12, 13 or 61 tumors from unexposed (n = 9) or plutonium-exposed dogs (n = 19). These data indicate that p53 and K-ras gene abnormalities as a result of missense mutation are infrequent events in spontaneous and 239PuO2-induced lung neoplasia in this colony of beagle dogs. Alternative mechanisms of gene alteration may be involved in canine pulmonary carcinogenesis.

Alpha Particles↗

PubMed1979

Cancer of the breast. Radiation therapy.

There are many questions that have to be answered concerning the role of radiotherapy in the management of primary breast cancer. Hopefully, prospective clinical trials will provide some answers, but more basic research into the biology of breast cancer and the host-tumor relationship will be needed. There are indications that radiotherapy alone, or following minimal extirpative surgery in selected cases, may be as effective for control of breast cancer as conventional mastectomies. The role of radiotherapy following segmental mastectomy, with or without axillary dissection, needs to be clarified. The possibility exists that high LET (linear energy transfer) radiation such as neutron or pi meson beams may provide better local control than conventional radiation. Thus, it may be possible to treat effectively all primary breast cancers with such radiations and obviate the need for any type of mastectomy. It remains to be demonstrated whether adjuvant chemotherapy is as effective as radiotherapy in preventing chest wall and regional node recurrences. If it is not, there may be a place for both adjuvant chemotherapy and radiotherapy in the treatment of operable cancer of the breast. Likewise, effective chemotherapy combined with radiotherapy may increase the local and regional control achieved with radiotherapy alone and make more primary lesions suitable for treatment without mastectomy. Meyer (1970) recently called attention to the leukopenia and cellualr immune deficiency produced by irradiation to the thorax and mediastinum. Further study is necessary to define exactly how much immunosuppression results from radiotherapy, its clinical significance and what can be done to avoid or counter it. If Stjervsward's thesis (1974) concerning the deleterious effects of radiotherapy on survival is correct, then it is of great importance to identify those patients most likely to be adversely affected by radiotherapy. Conversely, it may be possible in the future to identify a subgroup of patients who would not be adversely affected by radiation and who would be most likely to benefit from it.

Breast Neoplasms↗

PubMedDate not supplied

Critical evaluation of bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when 10B, a stable isotope, is irradiated with low energy neutrons to produce high linear energy transfer (LET) alpha particles and recoiling 7Li nuclei. In order for BNCT to be successful in treating cancer, approximately 10(9) boron atoms must be delivered per tumor cell to sustain a lethal 10B, (n,a) 7Li capture reaction. In the present study, we have produced and characterized a bispecific antibody (BsAbB8), which was reactive with both human glioma and melanoma cell lines, as well as with a variety of polyhedral borane anions (PBA). The affinity constants (KA) of BsAb-B8 with D-54 MG and M21 cells were 3.49 and 2.57 x 10(8) M-1, respectively, which were almost identical to those of the parental mAb 9.2.27 with these cell lines. In vivo tumor localizing properties were studied in nude mice bearing subcutaneous xenografts of the D-54 MG glioma. Following intravenous injection of 131I-labeled BsAb-B8, 3.4 +/- 0.2% of the injected dose/g was detected in the tumor at 24 hours, and then slowly declined to 2.0 +/- 0.4% at 96 hours compared to 1.34 +/- 0.07% and 0.03 +/- 0.01%, respectively, for normal mouse IgG. Based on the assumption that all the tumor cell antigenic receptor sites could be saturated, the following calculations have been carried out. The maximum concentration of BsAb-B8 that could be delivered to 1 g of D-54 MG glioma cells would be 99.6 micrograms, which could bind 71.7 ng of a PBA. However, since at least 500 x more boron would be required per gram of tumor to sustain a lethal 10B (n,a) 7Li capture reaction, a macromolecule containing -10(3)-10(4) boron atoms rather than a low molecular weight PBA would be required to deliver this amount. Such boron containing macromolecules have been synthesized by us, and future studies should provide information on the feasibility of using them in combination with BsAb-B8 to deliver the requisite amount of 10B.

Animals↗

PubMed1997

Delayed appearance of radiation-induced mutations at the Hprt locus in murine hemopoietic cells.

Earlier work in this laboratory identified high levels of non-clonal chromatid aberrations in the clonal descendants of murine hemopoietic stem cells after many cell divisions postirradiation with densely-ionizing, high linear energy transfer (LET) alpha-particles, but not with sparsely ionizing low LET X-rays. Using the Hprt locus as a marker, we have now demonstrated genomic instability in murine hemopoietic stem cells for greater than 20 cell divisions following both high and low LET irradiation. The increase in Hprt-deficient variants demonstrated following X- as well as alpha-particle and neutron irradiation indicates that there is a difference in the LET-dependence of delayed gene mutations and higher-order cytogenetic effects. Over 90% of the mutations identified arose in the expanding colonies after more than 12 cell divisions postirradiation and therefore cannot be attributed to the initial DNA damage. Such a high frequency of delayed mutations has important implications for mechanistic studies of radiation mutagenesis and for risk estimation.

Alpha Particles↗

PubMed1997

Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells.

The mechanism(s) by which high-linear energy transfer a particles, like those emitted by inhaled radon and radon daughters, cause lung cancer has not been elucidated. Conceivably, DNA damage that is induced by a particles may be mediated by the metabolic generation of reactive oxygen species (ROS), in addition to direct a particle-DNA interactions and hydroxyl radical-DNA interactions. Using normal human lung fibroblasts, we investigated the hypothesis that densely ionizing alpha particles may induce the intracellular generation of superoxide (O2.-) and hydrogen peroxide (H2O2). Ethidium bromide and 2',7'-dichlorofluorescein, fluorescent products of the membrane-permeable dyes hydroethidine and 2',7'-dichlorofluorescin diacetate, respectively, were used to monitor the intracellular production of O2.- and H2O2, respectively, by flow cytometry. Compared to sham-irradiated cells, fibroblasts that were exposed to alpha particles (0.4-19 cGy) had significant increases in intracellular O2.- production, along with concomitant increases in H2O2 production. Further analyses suggest that the plasma membrane-bound NADPH-oxidase is primarily responsible for this increased intracellular generation of ROS and that the ROS response does not require direct nuclear or cellular "hits" by the a particles. In this latter regard, we additionally report that unirradiated cells also show the ROS response when they are incubated with serum-containing culture medium that has been exposed to a particles or when they are incubated with supernatants from a-irradiated cells. Our overall results support the possibility that a particles, at least in part, may mediate their DNA-damaging effects indirectly via a ROS-related mechanism.

Alpha Particles↗

PubMed1997

Biodosimetry of ionizing radiation by selective painting of prematurely condensed chromosomes in human lymphocytes.

Painting of interphase chromosomes can be useful for biodosimetric purposes in particular cases such as radiation therapy, accidental exposure to very high radiation doses and exposure to densely ionizing radiation, for example during space missions. Biodosimetry of charged-particle radiation is analyzed in the present paper. Target cells were human peripheral blood lymphocytes irradiated in vitro with gamma rays, protons and iron ions. After exposure, lymphocytes were incubated for different times to allow repair of radiation-induced damage and then fused to mitotic hamster cells to promote premature condensation in the interphase chromosomes. Chromosome spreads were then hybridized with whole-chromosome DNA probes labeled with fluorescent stains. Dose-response curves for the induction of chromatin fragments shortly after exposure, as well as the kinetics of rejoining and misrejoining, were not markedly dependent on linear energy transfer. However, after exposure to heavy ions, more aberrations were scored in the interphase cells after incubation for repair than in metaphase samples harvested at the first postirradiation mitosis. On the other hand, no significant differences were observed in the two samples after exposure to sparsely ionizing radiation. These results suggest that interphase chromosome painting can be a useful tool for biodosimetry of particle radiation.

Animals↗

PubMed1997

Induction of chromosome aberrations in human cells by charged particles.

Chromosome aberrations induced by high-energy charged particles in normal human lymphocytes and human fibroblasts have been investigated. The charged particles included 250 MeV/nucleon protons, 290 MeV/nucleon carbon ions and 1 GeV/nucleon iron ions. The energies of the charged particles were higher than in most of the studies reported in the literature. Lymphocytes were stimulated to grow immediately after irradiation, while fibroblasts were incubated at 37 degrees C for 24 h for repair. Chromosomes were collected at the first mitosis after irradiation and chromosome aberrations were scored using the fluorescence in situ hybridization (FISH) technique with a whole-chromosome 4 probe. Chromosome aberrations were classified as reciprocal exchanges, incomplete exchanges, deletions and complex exchanges. The relative biological effectiveness (RBE) for each type of aberration was calculated by dividing a dose of 4 Gy by the dose of the charged particles producing the same effect as 4 Gy of gamma rays. Results of this study showed that complex aberrations have the highest RBE for radiation of high linear energy transfer (LET) for human lymphocytes, but for fibroblasts, the greatest effect was for incomplete exchanges. For both lymphocytes and fibroblasts, iron ions induced a similar fraction of aberrant cells.

Carbon↗

PubMed1997

Cell cycle regulation in irradiated and nonirradiated cells.

Exposure of cells to ionizing radiation induces damage in the DNA. The adverse consequences of such exposures depend on the amount of the DNA damage induced as determined by the absorbed dose, as well as by its form as determined by the linear energy transfer. In addition to physical determinants, biological factors critically affect radiation response. Cells have the ability to sense DNA damage, and to activate repair pathways that efficiently remove such damage and restore the integrity of the DNA. Highly sophisticated mechanisms further enable cells to actively stall growth and division after sensing DNA damage. Such inhibitory processes, termed checkpoints, may optimize repair and minimize the adverse consequences of DNA damage. We review the fundamental principles underlying checkpoints as they have emerged from active research in the last few years and discuss briefly their relevance to the practice of medical and radiation oncology.

Animals↗

PubMed1997

A rational approach to the treatment of prostate cancer with radiation therapy: lessons for the future.

The widespread use of prostate-specific antigen (PSA) has revealed that radiation therapy cures adenocarcinoma of the prostate less frequently than previously believed. Biologic factors (such as the complex nature of this disease) and technical factors (geographic miss, inadequate dose to the tumor volume) affect the ability of radiation to effectively treat all patients with prostate cancer. To improve treatment outcome, patients with virulent forms of the disease must be identified. The use of prognostic markers (PSA, prostate-specific membrane antigen, prostate-specific antigen doubling time) and genetic markers (12 lipoxygenase, p53, bcl-2, ploidy) may aid in the development of treatments for these patients. Technical modifications have been made to increase the total dose delivered to the prostate and the accuracy of dose delivery. Brachytherapy, proton therapy and conformal radiation therapy have been used to increase the relative integral dose. Improved prostate targeting may be achieved with the use of fiducial markers, on-line portal imaging, and endorectal magnetic resonance imaging. High linear energy transfer radiation, radiosensitizers and altered fractionation have been used in an attempt to increase the biologic equivalent dose to the tumor. Lastly, hormonal therapy and chemotherapy have been shown to decrease tumor burden and improve local control. All of these methods may improve outcome in patients with adenocarcinoma of the prostate. However, further work must be completed to translate these methods into standards of care.

Biomarkers, Tumor↗

PubMed1999

Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry.

UNLABELLED: The alpha-particle-emitting radionuclides have several physical characteristics that make them attractive candidates for radioimmunotherapy: (a) high linear energy transfer; (b) short path lengths (50-80 microm); and (c) limited ability of cells to repair damage to DNA. This article describes the pharmacokinetic, bioactivity, toxicity and chemical characteristics of alpha-particle-emitting, 213Bi and 212Bi radiometal conjugated HuM195 (anti-CD33) constructs. Conjugation of HuM195 to SCN-CHX-A-DTPA resulted in the attachment of up to 10 chelating ligand molecules per antibody. RESULTS: Radiolabeling efficiency of the CHX-A-DTPA-HuM195 construct with 213Bi was 78%+/-10% (n = 46) after 10 min at specific activities of up to 1110 MBq/mg. The immunoreactivity of the 213Bi-labeled CHX-A-DTPA-HuM195 construct was 84%+/-10% (n = 28) and was independent of the specific activity. The bismuth-labeled CHX-A-DTPA-HuM195 construct was rapidly internalized into the cell in a time-dependent manner ranging from 50% at 1 h to 65% at 24 h. 205Bi/206Bi-labeled constructs were stable for at least 2 d in vitro in the presence of human serum at 37 degrees C. After injection into mice, there was no uptake or loss of bismuth to mouse tissues, which do not express CD33, or to the kidney, which has avidity for free bismuth. Mice injected intraperitoneally with doses of (213Bi)CHX-A-DTPA-HuM1 95 ranging from 18.5 to 740 MBq/kg showed no toxicity, but at 2590 MBq/kg, two of the three mice died within 2 wk and a third mouse showed significant reductions in white blood cell counts. Mice injected intravenously with doses of (213Bi)CHX-A-DTPA-HuM195 up to 370 MBq/kg exhibited little toxicity, but 666 MBq/kg was above the MTD for mice. Leukemia cell killing in vitro with bismuth-labeled HuM1 95 showed dose- and specific activity-dependent killing of CD33+ HL60 cells; approximately 50% killing was observed when two bismuth atoms (50 fM radiolabeled antibody) were initially bound onto the target cell surface. CONCLUSION: Alpha-emitting antibodies are among the most potent cytotoxic agents known, yet are specific and appear safe in vivo. The physical and biochemical characteristics of the 213Bi isotope and its generation, as well as the biochemistry of the 213Bi-labeled CHX-A-DTPA-HuM195 construct, make it possible to use the constructs safely and feasibly in humans at therapeutic levels.

Alpha Particles↗